7-(substituted)-8-(substituted)-9-[(substituted glycyl)amido]-6-demethyl-6-deoxytetracyclines

ABSTRACT

The invention provides compounds of the formula: ##STR1## wherein R, R 3 , R 4 , X and W are defined in the specification. These compounds are useful as antibiotic agents.

This is a divisional of application Ser. No. 08/193,828 filed on Feb. 8,1994, now U.S. Pat. No. 5,386,041, which in turn is a divisional ofapplication Ser. No. 07/928,578 filed on Aug. 13, 1992, now U.S. Pat.No. 5,420,272.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to novel[4S-(4alpha,-12a-alpha)]-4-(dimethylamino)-7-(substituted)-8-(substituted)-9-[[(substitutedamino)substituted]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetra-hydroxy-1,11-dioxo-2-naphthacenecarboxamides,herein after called 7-(substituted)-8-(substituted)-9-[(substitutedglycyl)amido]-6-demethyl-6-deoxytetracyclines, which exhibit antibioticactivity against a wide spectrum of organisms including organisms whichare resistant to tetracyclines and are useful as antibiotic agents.

The invention also relates to novel9-[(haloacyl)amido]-7-(substituted)-8-(substituted)-6-demethyl-6-deoxytetracyclineintermediates useful for making the novel compounds of the presentinvention and to novel methods for producing the novel compounds andintermediate compounds.

SUMMARY OF THE INVENTION

This invention is concerned with novel7-(substituted)-8-(substituted)-9-[(substitutedglycyl)-amido]-6-demethyl-6-deoxytetracyclines, represented by formula Iand II, which have antibacterial activity; with method of treatinginfectious diseases in warm blooded animals employing these compounds;with pharmaceutical preparations containing these compounds; with novelintermediate compounds and processes for the production of thesecompounds. More particularly, this invention is concerned with compoundsof formula I and II which have enhanced antibiotic activity againsttetracycline resistant strains as well as a high level of activityagainst strains which are normally susceptible to tetracyclines.##STR2##

In formula I and II,

X is halogen or trifluoromethanesulfonyloxy, the halogen is selectedfrom bromine, chlorine, fluorine and iodine;

R is selected from hydrogen; halogen selected from bromine, chlorine,fluorine and iodine;

or R=--NR¹ R²

and when R=--NR¹ R²

and R¹ =hydrogen,

R² =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl,2-methylpropyl or 1,1-dimethylethyl;

and when R¹ =methyl or ethyl,

R² =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or2-methylpropyl;

and when R¹ =n-propyl,

R² =n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;

and when R¹ =1-methylethyl,

R² =n-butyl, 1-methylpropyl or 2-methylpropyl;

and when R¹ =n-butyl,

R² =n-butyl, 1-methylpropyl or 2-methylpropyl;

and when R¹ =1-methylpropyl,

R² =2-methylpropyl;

R³ is selected from hydrogen; straight or branched (C₁ -C₈)alkyl groupselected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl, heptyl and octyl; α-mercapto(C₁ -C₄)alkyl group selected frommercaptomethyl, α-mercaptoethyl, α-mercapto-1-methylethyl,α-mercaptopropyl and α-mercaptobutyl; α-hydroxy(C₁ -C₄)alkyl groupselected from hydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl,α-hydroxypropyl and α-hydroxybutyl; carboxyl(C₁ -C₈)alkyl group; (C₆-C₁₀)aryl group selected from phenyl, α-naphthyl and β-naphthyl;substituted(C₆ -C₁₀)aryl, group (substitution selected from hydroxy,halogen, (C₁ -C₄)alkoxy, trihalo(C₁ -C₃)alkyl, nitro, amino, cyano, (C₁-C₄)alkoxycarbonyl, (C₁ -C₃)alkylamino and carboxy); (C₇ -C₉)aralkylgroup selected from benzyl, 1-phenylethyl, 2-phenylethyl andphenylpropyl; substituted(C₇ -C₉) aralkyl group [substitution selectedfrom halo, (C₁ -C₄)alkyl, nitro, hydroxy, amino, mono- or disubstituted(C₁ -C₄)alkylamino, (C₁ -C₄)alkoxy, (C₁ -C₄)alkylsulfonyl, cyano andcarboxy];

R⁴ is selected from hydrogen and (C₁ -C₆)alkyl selected from methyl,ethyl propyl, isopropyl, butyl, isobutyl, pentyl and hexyl;

when R³ does not equal R⁴ the stereochemistry of the asymmetric carbon(i.e., the carbon bearing the W substituent) maybe be either theracemate (DL) or the individual enantiomers (L or D);

W is selected from amino; hydroxylamino; (C₁ -C₁₂) straight or branchedalkyl monosubstituted amino group substitution selected from methyl,ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl,1,1-dimethylethyl, n-pentyl, 2-methylbutyl, 1,1-dimethylpropyl,2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3-methylpentyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 1-methyl-1-ethylpropyl, heptyl, octyl, nonyl, decyl,undecyl and dodecyl and the diastereomers and enantiomers of saidbranched alkyl monosubstituted amino group; C₃ -C₈)cycloalkylmonosubstituted amino group substitution selected from cyclopropyl,trans-1,2-dimethylcyclopropyl, cis-1,2-dimethylcyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,bicyclo[2.2.1]-hept-2-yl, and bicyclo[2.2.2]oct-2-yl and thediastereomers and enantiomers of said C₃ -C₈)cycloalkyl monosubstitutedamino; [(C₄ -C₁₀)cycloalkyl]alkyl monosubstituted amino groupsubstitution selected from (cyclopropyl)methyl, (cyclopropyl)ethyl,(cyclobutyl)methyl, (trans-2-methylcyclopropyl)methyl, and(cis-2-methylcyclobutyl)methyl; (C₃ -C₁₀)alkenyl monosubstituted aminogroup substitution selected from allyl, 3-butenyl, 2-butenyl(cis ortrans), 2-pentenyl, 4-octenyl, 2,3-dimethyl-2-butenyl,3-methyl-2-butenyl, 2-cyclopentenyl and 2-cyclohexanyl; (C₆ -C₁₀)arylmonosubstituted amino group substitution selected from phenyl andnaphthyl; (C₇ -C₁₀)aralkylamino group substitution selected from benzyl,2-phenylethyl, 1-phenylethyl, 2-(naphthyl)methyl, 1-(naphthyl)methyl andphenylpropyl; substituted (C₆ -C₁₀)aryl monosubstituted amino group[substitution selected from (C₁ -C₅)acyl, (C₁ -C₅)acylamino, (C₁-C₄)alkyl, mono or disubstituted (C₁ -C₈)alkylamino, (C₁ -C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁ -C₄)alkylsulfonyl, amino, carbony, cyano,halogen, hydroxy, nitro and trihalo(C₁ -C₃)alkyl]; straight or branchedsymmetrical disubstituted (C₂ -C₁₄)alkylamino group substitutionselected from dimethyl, diethyl, diisopropyl, di-n-propyl, dibutyl anddiisobutyl; symmetrical disubstituted (C₃ -C₁₄)cycloalkylamino groupsubstitution selected from dicyclopropyl, dicyclobutyl, dicyclopentyl,dicyclohexyl and dicycloheptyl; straight or branched unsymmetricaldisubstituted (C₃ -C₁₄)alkylamino group wherein the total number ofcarbons in the substitution is not more than 14; unsymmetricaldisubstituted (C₄ -C₁₄)cycloalkylamino group wherein the total number ofcarbons in the substitution is not more than 14; (C₂ -C₈)azacycloalkyland substituted (C₂ -C₈)azacycloalkyl group substitution selected fromaziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, 4-methylpiperidinyl,2-methylpyrrolidinyl, cis-3,4-dimethylpyrrolidinyl,trans-3,4-dimethylpyrrolidinyl, 2-azabicyclo[2.1.1]hex-2-yl,5-azabicyclo[2.1.1]hex-5-yl, 2-azabicyclo[2.2.1]-hept-2-yl,7-azabicyclo[2.2.1]hept-7-yl, 2-azabicyclo[2.2.2]oct-2-yl and thediastereomers and enantiomers of said (C₂ -C₈)azacycloalkyl andsubstituted (C₂ -C₈)azacycloalkyl group; 1-azaoxacycloalkyl selectedfrom morpholinyl and 1-aza-5-oxocycloheptane; substituted1-azaoxacycloalkyl group substitution selected from 2-(C₁-C₃)alkylmorpholinyl, 3-(C₁ -C₃)alkylisoxazolidinyl, tetrahydrooxazinyland 3,4-dihydrooxazinyl; [1,n]-diazacycloalkyl and substituted[1,n]-diazacycloalkyl group selected from piperazinyl, 2-(C₁-C₃)alkylpiperazinyl, 4-(C₁ -C₃)alkylpiperazinyl,2,4-dimethylpiperazinyl, 4-(C₁ -C₄)alkoxypiperazinyl, 4-(C₆-C₁₀)aryloxypiperazinyl, 4-hydroxypiperazinyl,2,5-diazabicyclo[2.2.1]hept-2-yl,2,5-diaza-5-methylbicyclo[2.2.1]hept-2-yl,2,3-diaza-3-methylbicyclo[2.2.2]oct-2-yl,2,5-diaza-5,7-dimethylbicyclo[2.2.2]oct-2-yl and the diastereomers orenantiomers of said [1,n]-diazacycloalkyl and substituted[1,n]-diazacycloalkyl group; 1-azathiacycloalkyl and substituted1-azathiacycloalkyl group selected from thiomorpholinyl, 2-(C₁-C₃)alkylthiomorpholinyl and 3-(C₃ -C₆)cycloalkylthiomorpholinyl;N-azolyl and substituted N-azolyl group selected from 1-imidazolyl,2-(C₁ -C₃)alkyl-1-imidazolyl, 3-(C₁ -C₃)alkyl-1-imidazolyl, 1-pyrrolyl,2-(C₁ -C₃)alkyl-1-pyrrolyl, 3-(C₁ -C₃)alkyl-1-pyrazolyl, indolyl,1-(1,2,3-triazolyl), 4-(C₁ -C₃ )alkyl-1-(1,2,3-triazolyl), 5-(C₁-C₃)alkyl-1-(1,2,3-triazolyl), 4-(1,2,4-triazolyl, 1-tetrazolyl,2-tetrazolyl and benzimidazolyl; (heterocycle)amino group selected from2- or 3-furanylamino, 2- or 3-thienylamino, 2-, 3- or 4-pyridylamino, 2-or 5-pyridazinylamino, 2-pyrazinylamino, 2-(imidazolyl)amino,(benzimidazolyl)amino, and (benzothiazolyl)amino and substituted(heterocycle)amino group as defined above with substitution selectedfrom straight or branched (C₁ -C₆)alkyl; (heterocycle)methylamino groupselected from 2- or 3-furylmethylamino, 2- or 3-thienylmethylamino, 2-,3- or 4-pyridylmethylamino, 2- or 5-pyridazinylmethylamino,2-pyrazinylmethylamino, 2-(imidazolyl)methylamino,(-benzimidazolyl)methylamino, and (benzothiazolyl)methylamino andsubstituted (heterocycle)methylamino group as defined above withsubstitution selected from straight or branched (C₁ -C₆)alkyl;carboxy(C₂ -C₄)alkylamino group selected from aminoacetic acid,α-aminopropionic acid, β-aminopropionic acid, α-butyric acid, andβ-aminobutyric acid and the enantiomers of said carboxy(C₂-C₄)alkylamino group; (C₁ -C₄)alkoxycarbonylamino group substitutionselected from methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl,propoxycarbonyl, isoproproxycarbonyl, 1,1-dimethylethoxycarbonyl,n-butoxycarbonyl, and 2-methylpropoxycarbonyl; (C₁ -C₄)alkoxyamino groupsubstitution selected from methoxy, ethoxy,n-propoxy, 1-methylethoxy,n-butoxy, 2-methylpropoxy, and 1,1-dimethylethoxy; (C₃-C₈)cycloalkoxyamino group selected from cyclopropoxy,trans-1,2-dimethylcyclopropoxy, cis-1,2-dimethylcyclopropoxy,cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, cyclooctoxy,bicyclo[2.2.1]hept-2-yloxy, bicyclo[2.2.2]oct-2-yloxy and thediastereomers and enantiomers of said (C₃ -C₈)cycloalkoxyamino group;(C₆ -C₁₀)aryloxyamino group selected from phenoxyamino,1-naphthyloxyamino and 2-naphthyloxyamino; (C₇ -C₁₁)arylalkoxyaminogroup substitution selected from benzyloxy, 2-phenylethoxy,1-phenylethoxy, 2-(naphthyl)methoxy, 1-(naphthyl)methoxy andphenylpropoxy;

R⁵ is selected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)arylgroup selected from phenyl, α-naphthyl or β-naphthyl; (C₇ -C₉)aralkylgroup such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; aheterocycle group selected from a five membered aromatic or saturatedring with one N, O, S or Se heteroatom optionally having a benzo orpyrido ring fused thereto: ##STR3## such as pyrrolyl, N-methylindolyl,indolyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl,tetrahydrofuranyl, furanyl, benzofuranyl, tetrahydrothienyl, thienyl,benzothienyl or selenazolyl, or a five membered aromatic ring with twoN, O, S or Se heteroatoms optionally having a benzo or pyrido ring fusedthereto: ##STR4##

    Z or Z.sup.1 =N, O, S or Se

such as imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl,indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridylor pyridylimidazolyl, or a five membered saturated ring with one or twoN, O, S or Se heteroatoms and an adjacent appended O heteroatom:##STR5## (A is selected from hydrogen; straight or branched (C₁-C₄)alkyl; C₆ -aryl; substituted C₆ -aryl (substitution selected fromhalo,(C₁ -C₄)alkoxy, trihalo(C₁ -C₃)alkyl, nitro, amino, cyano, (C₁-C₄)alkoxycarbonyl, (C₁ -C₃)alkylamino or carboxy); (C₇ -C₉)aralkylgroup selected from benzyl, 1-phenylethyl, 2-phenylethyl orphenylpropyl)

such as γ-butyrolactam, γ-butyrolactone, imidazolidinone orN-aminoimidazolidinone, or a six membered aromatic ring with one tothree N heteroatoms such as pyridyl, pyridazinyl, pyrazinyl,sym-triazinyl, unsym-triazinyl, pyrimidinyl or (C₁-C₃)alkylthiopyridazinyl, or a six membered saturated ring with one ortwo N, O, S or Se heteroatoms and an adjacent appended 0 heteroatom suchas 2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-2-dioxo-1-piperazinyl,2-dioxomorpholinyl, 2-dioxothiomorpholinyl; or --(CH₂)_(n) COOR⁷ wheren=0-4 and R⁷ is selected from hydrogen; straight or branched (C₁-C₃)alkyl group selected from methyl, ethyl, n-propyl or 1-methylethyl;or (C₆ -C₁₀)aryl group selected from phenyl, α-naphthyl, or β-naphthyl;

R⁶ is selected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)arylgroup-selected from phenyl, α-naphthyl or β-naphthyl; (C₇ -C₉)aralkylgroup such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; aheterocycle group selected from a five membered aromatic or saturatedring with one N, O, S or Se heteroatom optionally having a benzo orpyrido ring fused thereto: ##STR6##

    Z=N, O, S or Se

such as pyrrolyl,-N-methylindolyl, indolyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl,tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, or a fivemembered aromatic ring with two N, O, S or Se heteroatoms optionallyhaving a benzo or pyrido ring fused thereto: ##STR7##

    Z or Z.sup.1 =N, O, S or Se

such as imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl,indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridylor pyridylimidazolyl, or a five membered saturated ring with one or twoN, O, S or Se heteroatoms and an adjacent appended O heteroatom:##STR8## (A is selected from hydrogen; straight or branched (C₁-C₄)alkyl; C₆ -aryl; substituted C₆ -aryl (substitution selected fromhalo,(C₁ -C₄)alkoxy, trihalo(C₁ -C₃)alkyl, nitro, amino, cyano, (C₁-C₄)alkoxycarbonyl, (C₁ -C₃)alkylamino or carboxy); (C₇ -C₉)aralkylgroup selected from benzyl, 1-phenylethyl, 2-phenylethyl orphenylpropyl)

such as γ-butyrolactam, γ-butyrolactone, imidazolidinone orN-aminoimidazolidinone, or a six membered aromatic ring with one tothree N heteroatoms such as pyridyl, pyridazinyl, pyrazinyl,sym-triazinyl, unsymtriazinyl, pyrimidinyl or (C₁-C₃)alkylthiopyridazinyl.sub., or a six membered saturated ring with oneor two N, O, S or Se heteroatoms and an adjacent appended O heteroatomsuch as 2,3-dioxo-1-piperazinyl, 4-ethyl-2,3-dioxo-1-piperazinyl,4-methyl-2,3-dioxo-1-piperazinyl, 4-cyclopropyl-2-dioxo-1-piperazinyl,2-dioxomorpholinyl, 2-dioxothiomorpholinyl; or --(CH₂)_(n) COOR⁷ wheren=0-4 and R⁷ is selected from hydrogen; straight or branched (C₁-C₃)alkyl selected from methyl, ethyl, n-propyl or 1-methylethyl; or (C₆-C₁₀)aryl selected from phenyl, α-naphthyl or β-naphthyl; with theproviso that R⁵ and R⁶ cannot both be hydrogen; or R⁵ and R⁶ takentogether are --(CH₂)₂ B(CH₂)₂ --, wherein B is selected from (CH₂)_(n)and n=0-1, --NH, --N(C₁ -C₃)alkyl [straight or branched], --N(C₁-C₄)alkoxy, oxygen, sulfur or substituted congeners selected from (L orD)proline, ethyl(L or D)prolinate, morpholine, pyrrolidine orpiperidine; and the pharmacologically acceptable organic and inorganicsalts or metal complexes.

Preferred compounds are compounds according to the above formula I andII wherein: X is halogen or trifluoromethanesulfonyloxy, the halogen isselected from bromine, chlorine, fluorine and iodine; R is selected fromhydrogen; halogen selected from bromine, chlorine and iodine;

or R=--NR¹ R²

and when R=--NR¹ R²

and R¹ =hydrogen,

R² =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or2-methylpropyl;

and when R¹ =methyl or ethyl,

R² =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or2-methylpropyl;

R³ is selected from hydrogen; straight or branched (C₁ -C₈)alkyl groupselected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl, heptyl and octyl; α-hydroxy(C₁ -C₄)alkyl group selected fromhydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl, α-hydroxypropyland α-hydroxybutyl; carboxyl(C₁ -C₈)alkyl group; (C₆ -C₁₀)aryl groupselected from phenyl, α-naphthyl and β-naphthyl; substituted(C₆-C₁₀)aryl group (substitution selected from hydroxy, halogen, (C₁-C₄)alkoxy, (C₁ -C₄)alkoxycarbonyl, and carboxy); (C₇ -C₉)aralkyl groupselected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl;substituted(C₇ -C₉)aralkyl group [substitution selected from halo, (C₁-C₄)alkyl, (C₁ -C₄)alkoxy, (C₁ -C₄)alkylsulfonyl, cyano and carboxy];

R⁴ is selected from hydrogen and (C₁ -C₄)alkyl selected from methyl,ethyl propyl, isopropyl, butyl and isobutyl;

when R³ does not equal R⁴ the stereochemistry of the asymmetric carbon(i.e., the carbon bearing the W substituent) maybe be either theracemate (DL) or the individual enantiomers (L or D);

W is selected from amino; hydroxylamino; (C₁ -C₁₂) straight or branchedalkyl monosubstituted amino group substitution selected from methyl,ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl,1,1-dimethylethyl, n-pentyl, 2-methylbutyl, 1,1-dimethylpropyl,2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3-methylpentyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 1-methyl-l-ethylpropyl, heptyl, octyl, nonyl, decyland the diastereomers and enantiomers of said branched alkylmonosubstituted amino group; (C₃ -C₈)cycloalkyl monosubstituted aminogroup substitution selected from cyclopropyl,trans-1,2-dimethylcyclopropyl, cis-1,2-dimethylcyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the diastereomersand enantiomers of said (C₃ -C₈)cycloalkyl monosubstituted amino group;[(C₄ -C₁₀)cycloalkyl]alkyl monosubstituted amino group substitutionselected from (cyclopropyl)methyl, (cyclopropyl)ethyl,(cyclobutyl)methyl, (trans-2-methylcyclopropyl)methyl and(cis-2-methylcyclobutyl)methyl; (C₃ -C₁₀)alkenyl monosubstituted aminogroup substitution selected from allyl, 3-butenyl, 2-butenyl (cis ortrans), 2-pentenyl, ¢-octenyl, 2,3-dimethyl-2-butenyl,3-methyl-2-butenyl, 2-cyclopentenyl and 2-cyclohexenyl; (C₇-C_(1O))aralkylamino group substitution selected from benzyl,2-phenylethyl, 1-phenylethyl, 2-(naphthyl)methyl, 1-(naphthyl)methyl andphenylpropyl; straight or branched symmetrical disubstituted (C₂-C₁₄)alkylamino group substitution selected from dimethyl, diethyl,diisopropyl, di-n-propyl, dibutyl and diisobutyl; symmetricaldisubstituted (C₃ -C₁₄)cycloalkylamino group substitution selected fromdicyclopropyl, dicyclobutyl, dicyclopentyl, dicyclohexyl anddicycloheptyl; straight or branched unsymmetrical disubstituted (C₃-C₁₄)alkyl amino group wherein the total number of carbons in thesubstitution is not more than 14; unsymmetrical disubstituted (C₄-C₁₄)cycloalkylamino group wherein the total number of carbons in thesubstitution is not more than 14; (C₂ -C₈)azacycloalkyl and substituted(C₂ -C₈)azacycloalkyl group substitution selected from aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, 4-methylpiperidinyl,2-methylpyrrolidinyl, cis-3,4-dimethylpyrrolidinyl,trans-3,4-dimethylpyrrolidinyl, 2-azabicyclo[2.1.1]hex-2-yl,5-azabicyclo[2.1.1]hex-5-yl, 2-azabicyclo[2.2.1]hept-2-yl,7-azabicyclo[2.2.1]hept- 7-yl, 2-azabicyclo[2.2.2]oct-2-yl and thediastereomers and enantiomers of said (C₂ -C₈)azacycloalkyl andsubstituted (C₂ -C₈)azacycloalkyl group; 1-azaoxacycloalkyl selectedfrom morpholinyl and 1-aza-5-oxocycloheptane; substituted1-azaoxacycloalkyl group substitution selected from 2-(C₁-C₃)alkylmorpholinyl, 3-(C₁ -C₃)alkylisoxazolidinyl, tetrahydrooxazinyland 3,4-dihydrooxazinyl; [1,n]-diazacycloalkyl and substituted[1,n]-diazacycloalkyl group selected from piperazinyl, 2-(C₁-C₃)alkylpiperazinyl, 4-(C₁ -C₃)alkylpiperazinyl,2,4-dimethylpiperazinyl, 4-(C₁ -C₄)alkoxypiperazinyl,2,5-diazabicyclo[2.2.1]hept-2-yl,2,5-diaza-5-methylbicyclo[2.2.1]hept-2-yl,2,3-diaza-3-methylbicyclo[2.2.2]oct-2-yl, and the diastereomers orenantiomers of said [1,n]-diazacycloalkyl and substituted[1,n]-diazacycloalkyl-group; 1-azathiacycloalkyl and substituted1-azathiacycloalkyl group selected from thiomorpholinyl, 2-(C₁-C₃)alkylthiomorpholinyl and 3-(C₃ -C₆)cycloalkylthiomorpholinyl;N-azolyl and substituted N-azolyl group selected from 1-imidazolyl,2-(C₁ -C₃)alkyl-1-imidazolyl, 3-(C₁ -C₃)alkyl-1-imidazolyl, 1-pyrrolyl,2-(C₁ -C₃)alkyl-1-pyrrolyl, 3-(C₁ -C₃)alkyl-1-pyrazolyl, indolyl,1-(1,2,3-triazolyl), 4-(C₁ -C₃)alkyl-1-(1,2,3-triazolyl), 5-(C₁-C₃)alkyl-1-(1,2,3-triazolyl) and 4-(1,2,4-triazolyl);(heterocycle)methylamino group said heterocycle selected from 2- or3-furylmethylamino, 2- or 3-thienylmethylamino, 2-, 3- or4-pyridylmethylamino, 2- or 5-pyridazinylmethylamino,2-pyrazinylmethylamino, 2-(imidazolyl)methylamino,(benzimidazolyl)methylamino, and (benzothiazolyl)methylamino andsubstituted (heterocycle)amino group as defined above with substitutionselected from straight or branched (C₁ -C₆)alkyl; carboxy(C₂ -C₄)alkylamino group selected from aminoacetic acid, α-aminopropionicacid, β-aminopropionic acid, α-butyric acid, β-aminobutyric acid and theenantiomers of said carboxy(C₂ -C₄)alkylamino group; (C₁-C₄)alkoxycarbonylamino group substitution selected frommethoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl, propoxycarbonyl,isoproproxycarbonyl, 1,1-dimethylethoxycarbonyl, n-butoxycarbonyl, and2-methylpropoxycarbonyl; (C₁ -C₄)alkoxyamino group substitution selectedfrom methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy,2-methylpropoxy, and 1,1-dimethylethoxy; C₃ -C₈)cycloalkoxyamino groupselected from cyclopropoxy, trans-1,2-dimethylcyclopropoxy,cis-1,2-dimethylcyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy,cycloheptoxy, cyclooctoxy, bicyclo[2.2.1]hept-2-yloxy,bicyclo[2.2.2]oct-2-yloxy and the diastereomers and enantiomers of saidC₃ -C₈)cycloalkoxyamino group; (C₇ -C₁₁)arylalkoxyamino groupsubstitution selected from benzyloxy, 2-phenylethoxy, 1-phenylethoxy,2-(naphthyl)methoxy, 1-(naphthyl)methoxy and phenylpropoxy;

R⁵ is selected from hydrogen; straight or branched. (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)arylgroup selected from phenyl, α-naphthyl or β-naphthyl; (C₇ -C₉)aralkylgroup such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; aheterocycle group selected from a five membered aromatic or saturatedring with one N, O, S or Se heteroatom optionally having a benzo orpyrido ring fused thereto: ##STR9##

    Z=N, O, S or Se

such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl,tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, or a fivemembered aromatic ring with two N, O, S or Se heteroatoms optionallyhaving a benzo or pyrido ring fused thereto: ##STR10##

    Z or Z.sup.1 =N, O, S or Se

such as imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl,indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridylor pyridylimidazolyl, or a five membered saturated ring with one or twoN, O, S or Se heteroatoms and an adjacent appended O heteroatom:##STR11## (A is selected from hydrogen; straight or branched (C₁-C₄)alkyl; C₆ -aryl; (C₇ -C₉)aralkyl group selected from benzyl,1-phenylethyl, 2-phenylethyl or phenylpropyl)

such as γ-butyrolactam, γ-butyrolactone, imidazolidinone orN-aminoimidazolidinone, or a six membered aromatic ring with one tothree N heteroatoms such as pyridyl, pyridazinyl, pyrazinyl,sym-triazinyl, unsymtriazinyl, pyrimidinyl or (C₁-C₃)alkylthiopyridazinyl; or --(CH₂)_(n) COOR⁷ where n=0-4 and R⁷ isselected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; or (C₆ -C₁₀)arylgroup selected from phenyl, α-naphthyl, or β-naphthyl;

R⁶ is selected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)arylgroup selected from phenyl, α-naphthyl or β-naphthyl; (C₇ -C₉)aralkylgroup such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; aheterocycle group selected from a five membered aromatic or saturatedring with one N, O, S or se heteroatom optionally having a benzo orpyrido ring fused thereto: ##STR12##

    Z=N, O, S or Se

such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl,tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, or a fivemembered aromatic ring with two N, O, S or Se heteroatoms optionallyhaving a benzo or pyrido ring fused thereto: ##STR13##

    Z or Z.sup.1 =N, O, S or Se

such as imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl,indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridylor pyridylimidazolyl, or a five membered saturated ring with one or twoN, O, S or Se heteroatoms and an adjacent appended O heteroatom:##STR14## (A is selected from hydrogen; straight or branched (C₁ -C₄)alkyl; C₆ -aryl; (C₇ -C₉) aralkyl group selected from benzyl,1-phenylethyl, 2-phenylethyl or phenylpropyl) such as γ-butyrolactam,γ-butyrolactone, imidazolidinone or N-aminoimidazolidinone, or a sixmembered aromatic ring with one to three N heteroatoms such as pyridyl,pyridazinyl, pyrazinyl, sym-triazinyl, unsymtriazinyl, pyrimidinyl or(C₁ -C₃)alkylthiopyridazinyl; or --(CH₂)_(n) COOR7 where n=0-4 and R⁷ isselected from hydrogen; straight or branched (C₁ -C₃)alkyl selected frommethyl, ethyl, n-propyl or 1-methylethyl; or (C₆ -C₁₀)aryl selected fromphenyl, α-naphthyl or β-naphthyl; with the proviso that R⁵ and R⁶ cannotboth be hydrogen; or R⁵ and R⁶ taken together are --(CH₂)₂ B(CH₂)₂ --,wherein B is selected from (CH₂)_(n) and n=0-1, --NH, --N(C₁ -C₃)alkyl[straight or branched], --N(C₁ -C₄)alkoxy, oxygen, sulfur or substitutedcongeners selected from (L or D)proline, ethyl(L or D)prolinate,morpholine, pyrrolidine or piperidine; and the pharmacologicallyacceptable organic and inorganic salts or metal complexes.

Particularly preferred compounds are compounds according to the aboveformula I and II wherein:

X is halogen or trifluoromethanesulfonyloxy, the halogen is selectedfrom bromine, chlorine, fluorine and iodine; R is selected fromhydrogen; halogen selected from bromine, chlorine and iodine;

or R=--NR¹ R²

and when R=--NR¹ R²

and R¹ =hydrogen,

R² =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl,2-methylpropyl or 1,1-dimethylethyl;

and when R¹ =methyl or ethyl,

R² =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or2-methylpropyl;

R³ is selected from hydrogen; straight or branched (C₁ -C₆)alkyl groupselected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyland hexyl; (C₆ -C₁₀)aryl group selected from phenyl, α-naphthyl andβ-naphthyl; (C₇ -C₉)aralkyl group selected from benzyl, 1-phenylethyl,2-phenylethyl and phenylpropyl;

R⁴ is selected from hydrogen and (C₁ -C₄)alkyl selected from methyl,ethyl propyl, isopropyl, butyl and isobutyl;

when R³ does not equal R⁴ the stereochemistry of the asymmetric carbon(i.e., the carbon bearing the W substituent) maybe be either theracemate (DL) or the individual enantiomers (L or D);

W is selected from amino; (C₁ -C₁₂) straight or branched alkylmonosubstituted amino group substitution selected from methyl, ethyl,n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl,1,1-dimethylethyl, n-pentyl, 2-methylbutyl, 1,1-dimethylpropyl,2,2-dimethylpropyl, 3-methylbutyl,n-hexyl, 1-methylpentyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3-methylpentyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 1-methyl-1-ethylpropyl and the diastereomers andenantiomers of said branched alkyl monosubstituted amino group; (C₃-C₅)cycloalkyl monosubstituted amino group substitution selected fromcyclopropyl, trans-1,2-dimethylcyclopropyl, cis-1,2-dimethylcyclopropyl,cyclobutyl and the diastereomers and enantiomers of said (C₃-C₅)cycloalkyl monosubstituted amino group; [(C₄ -C₁₀)cycloalkyl]alkylmonosubstituted amino group substitution selected from(cyclopropyl)methyl, (cyclopropyl)ethyl and (cyclobutyl)methyl; (C₃-C₁₀)alkenyl monosubstituted amino group substitution selected fromallyl, 3-butenyl, 2-butenyl (cis or trans), 2-pentenyl, 4-octenyl,2,3-dimethyl-2-butenyl, 3-methyl-2-butenyl, 2-cyclopentenyl and2-cyclohexenyl; (C₇ -C₁₀)aralkylamino group substitution selected frombenzyl, 2-phenylethyl, 1-phenylethyl, 2-(naphthyl)methyl,1-(naphthyl)methyl and phenylpropyl; straight or branched symmetricaldisubstituted (C₂ -C₁₄)alkylamino group substitution selected fromdimethyl, diethyl, diisopropyl, and di-n-propyl; straight or branchedunsymmetrical disubstituted (C₃ -C₁₄)alkylamino group wherein the totalnumber of carbons in the substitution is no more than 14; unsymmetricaldisubstituted (C₄ -C₁₄)cycloalkylamino group wherein the total number ofcarbons in the substitution is no more than 14; (C₂ -C₈)azacycloalkyland substituted (C₂ -C₈)azacycloalkyl group substitution selected fromaziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, 4-methylpiperidinyl,2-methylpyrrolidinyl, cis-3,4-dimethylpyrrolidinyl,trans-3,4-dimethylpyrrolidinyl and the diastereomers and enantiomers ofsaid (C₂ -C₈)azacycloalkyl and substituted (C₂ -C₈)azacycloalkyl group;1-azaoxacycloalkyl selected from morpholinyl and1-aza-5-oxocycloheptane; substituted 1-azaoxacycloalkyl groupsubstitution selected from 2-(C₁ -C₃)alkylmorpholinyl, 3-(C₁-C₃)alkylisoxazolidinyl and tetrahydrooxazinyl; [1,n]-diazacycloalkyland substituted [1,n]-diazacycloalkyl group selected from piperazinyl,2-(C₁ -C₃)alkylpiperazinyl, 4-(C₁ -C₃)alkylpiperazinyl,2,4-dimethylpiperazinyl, 2,5-diazabicyclo[2.2.1]hept-2-yl,2,5-diaza-5-methylbicyclo[2.2.1]-hept-2-yl,2,3-diaza-3-methylbicyclo[2.2.2]oct-2-yl, and the diastereomers orenantiomers of said [1,n]-diazacycloalkyl and substituted[1,n]-diazacycloalkyl group; 1-azathiacycloalkyl and substituted1-azathiacycloalkyl group selected from thiomorpholinyl and 2-(C₁-C₃)alkylthiomorpholinyl; N-azolyl and substituted N-azolyl groupselected from 1-imidazolyl, indolyl, 1-(1,2,3-triazolyl) and4-(1,2,4-triazolyl); (heterocycle)methylamino group selected from 2- or3-furylmethylamino, 2- or 3-thienylmethylamino and 2-, 3- or4-pyridylmethylamino; (C₁ -C₄)alkoxycarbonylamino group substitutionselected from methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl,propoxycarbonyl, isoproproxycarbonyl, 1,1-dimethylethoxycarbonyl,n-butoxycarbonyl, and 2-methylpropoxycarbonyl; (C₁ -C₄)alkoxyamino groupsubstitution selected from methoxy, ethoxy, n-propoxy, 1-methylethoxy,n-butoxy, 2-methylpropoxy, and 1,1-dimethylethoxy; (C₇-C₁₁)arylalkoxyamino group substitution selected from benzyloxy,2-phenylethoxy, 1-phenylethoxy, 2-(naphthyl)methoxy, 1-(naphthyl)methoxyand phenylpropoxy;

R⁵ is selected from hydrogen; straight or branched. (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)arylgroup selected from phenyl, α-naphthyl or β-naphthyl; (C₇ -C₉)aralkylgroup such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; aheterocycle group selected from a five membered aromatic or saturatedring with one N, O, S or Se heteroatom optionally having a benzo orpyrido ring fused thereto: ##STR15##

    Z=N, O, S or Se

such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl,tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, or a fivemembered aromatic ring with two N, O, S or Se heteroatoms optionallyhaving a benzo or pyrido ring fused thereto: ##STR16##

    Z or Z.sup.1 =N, O, S or Se

such as imidazolyl, pyrazoly1, benzimidazolyl, oxazolyl, benzoxazolyl,indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridylor pyridylimidazolyl; or --(CH₂)_(n) COOR7 where n=0-4 and R⁷ isselected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; or (C₆ -C₁₀)arylgroup selected from phenyl, α-naphthyl, or β-naphthyl;

R⁶ is selected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)arylgroup selected from phenyl, α-naphthyl or β-naphthyl; (C₇ -C₉)aralkylgroup such as benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; aheterocycle group selected from a five membered aromatic or saturatedring with one N, O, S or Se heteroatom optionally having a benzo orpyrido ring fused thereto: ##STR17##

    Z=N, O, S or Se

such as pyrrolyl, N-methylindolyl, indolyl, 2-pyrrolidinyl,3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl, furanyl, benzofuranyl,tetrahydrothienyl, thienyl, benzothienyl or selenazolyl, or a fivemembered aromatic ring with two N, O, S or Se heteroatoms optionallyhaving a benzo or pyrido ring fused thereto: ##STR18##

    Z or Z.sup.1 =N, O, S or Se

such as imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl, benzoxazolyl,indazolyl, thiazolyl, benzothiazolyl, 3-alkyl-3H-imidazo[4,5-b]pyridylor pyridylimidazolyl; or --(CH₂)_(n) COOR7 where ns=0-4 and R⁷ isselected from hydrogen; straight or branched (C₁ -C₃)alkyl selected frommethyl, ethyl, n-propyl or 1-methylethyl; or (C₆ -C₁₀)aryl selected fromphenyl, α-naphthyl or β-naphthyl; with the proviso that R⁵ and R⁶ cannotboth be hydrogen; or R⁵ and R⁶ taken together are --(CH₂)₂ B(CH₂)₂ --,wherein B is selected from (CH₂)_(n) and n=0-1, --NH, --N(C₁ -C₃)alkyl[straight or branched], --N(C₁ -C₄)alkoxy, oxygen, sulfur or substitutedcongeners selected from (L or D)proline, ethyl(L or D)prolinate,morpholine, pyrrolidine or piperidine; and the pharmacologicallyacceptable organic and inorganic salts or metal complexes.

Compounds of special interest are compounds according to the aboveformula I and II wherein: X is halogen or trifluoromethanesulfonyloxy,the halogen is selected from chlorine and fluorine; R is selected fromhydrogen; halogen selected from chlorine and iodine; or

R=---NR¹ R²

and when R=--NR¹ R²

and R¹ =methyl or ethyl,

R² =methyl and ethyl;

R³ is selected from hydrogen; straight or branched (C₁ -C₂)alkyl groupselected from methyl and ethyl;

R⁴ is selected from hydrogen and (C₁ -C₆)alkyl selected from methyl andethyl;

when R³ does not equal R⁴ the stereochemistry of the asymmetric carbon(i.e., the carbon bearing the W substituent) maybe be either theracemate (DL) or the individual enantiomers (L or D);

W is selected from amino; (C₁ -C₄)straight or branched alkylmonosubstituted amino group substitution selected from methyl, ethyl,n-propyl, 1-methylethyl, n-butyl and 1-methylpropyl; (C₃ -C₄)cycloalkylmonosubstituted amino group substitution selected from cyclopropyl andcyclobutyl; (C₂ -C₈)azacycloalkyl and substituted (C₂ -C₈)azacycloalkylselected from pyrrolidinyl, piperidinyl and 4-methylpiperidinyl;1-azaoxacycloalkyl selected from morpholinyl; [1,n]-diazacycloalkyl andsubstituted [1,n]-diazacycloalkyl group selected from piperazinyl and4-(C₁ -C₃)alkylpiperazinyl; N-azolyl and substituted N-azolyl groupselected from 1-imidazolyl, 2-(C₁ -C₃)alkyl-1-imidazolyl and 3-(C₁-C₃)alkyl-1-imidazolyl; (heterocycle)methylamino group said heterocycleselected from 2-, 3- or 4-pyridylmethylamino; carboxy(C₂ -C₄)alkylaminogroup selected from aminoacetic acid, α-aminopropionic acid,β-aminopropionic acid, α-butyric acid, β-aminobutyric acid and theenantiomers of said carboxy(C₂ -C₄)alkylamino group;

R⁵ is selected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl;

R⁶ is selected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; with the provisothat R⁵ and R⁶ cannot both be hydrogen; or R⁵ and R⁶ taken from(CH2)_(n) and n=0-1, -NH, -N(C₁ l ) together are --(CH₂)₂ B(CH₂)₂ --,wherein B is selected from (CH₂)_(n) and n=0-1, --NH, --N(C₁ -C₃)alkyl[straight or branched], --N(C₁ -C₄)alkoxy, oxygen, sulfur or substitutedcongeners selected from (L or D)proline, ethyl(L or D)prolinate,morpholine, pyrrolidine or piperidine; and the pharmacologicallyacceptable organic and inorganic salts or metal complexes.

Also included in the present invention are compounds useful asintermediates for producing the above compounds of formula I and II.Such intermediates include those having the formula III: ##STR19##wherein:

Y is selected from (CH₂)_(n) X', n=0-5, X' is halogen selected frombromine, chlorine, fluorine and iodine; X is halogen ortrifluoromethanesulfonyl, the halogen is selected from bromine,chlorine, fluorine and iodine. R is selected from hydrogen; halogenselected from bromine, chlorine, fluorine and iodine;

or R=--NR¹ R²

and when R=--NR¹ R²

and R¹ =hydrogen,

R² =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl,2-methylpropyl or 1,1-dimethylethyl; and when R¹ =methyl or ethyl,

R² =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or2-methylpropyl; and when R¹ =n-propyl,

R² =n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl;

and when R¹ =1-methylethyl,

R² =n-butyl, 1-methylpropyl or 2-methylpropyl;

and when R¹ =n-butyl,

R² =n-butyl, 1-methylpropyl or 2-methylpropyl;

and when R¹ =1-methylpropyl,

R² =2-methylpropyl;

R³ is selected from hydrogen; straight or branched (C₁ -C₈)alkyl groupselected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl, heptyl and octyl; α-mercapto(C₁ -C₄)alkyl group selected frommercaptomethyl, α-mercaptoethyl, α-mercapto-1-methylethyl,α-mercaptopropyl and α-mercaptobutyl; α-hydroxy(C₁ -C₄)alkyl groupselected from hydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl,α-hydroxypropyl and α-hydroxybutyl; carboxyl(C₁ -C₈)alkyl group; (C₆-C₁₀)aryl group selected from phenyl, α-naphthyl and β-naphthyl;substituted(C₆ -C₁₀)aryl group (substitution selected from hydroxy,halogen, (C₁ -C₄)alkoxy, trihalo(C₁ -C₃)alkyl, nitro, amino, cyano, (C₁-C₄)alkoxycarbonyl, (C₁ -C₃)alkylamino and carboxy); (C₇ -C₉)aralkylgroup selected from benzyl, 1-phenylethyl, 2-phenylethyl andphenylpropyl; substituted(C₇ -C₉)aralkyl group [substitution selectedfrom halo, (C₁ -C₄)alkyl, nitro, hydroxy, amino, mono- or disubstituted(C₁ -C₄)alkylamino, (C₁ -C₄)alkoxy, (C₁ -C₄)alkylsulfonyl, cyano andcarboxy];

R⁴ is selected from hydrogen and (C₁ -C₆)alkyl selected from methyl,ethyl propyl, isopropyl, butyl, isobutyl, pentyl and hexyl;

when R³ does not equal R⁴ the stereochemistry of the asymmetric carbon(i.e., the carbon bearing the W substituent) maybe be either theracemate (DL) or the individual enantiomers (L or D); and the pharmacologically acceptible organic and inorganic salts or metal complexes.

Preferred compounds are compounds according to the above formula IIIwherein:

Y is selected from (CH₂)_(n) X', n=0-5, X' is halogen selected frombromine, chlorine, flourine and iodine;

X is halogen or trifluoromethanesulfonyloxy, the halogen is selectedfrom bromine, chlorine, fluorine and iodine;

R is selected from hydrogen; halogen selected from bromine, chlorine andiodine;

or R=--NR¹ R²

and when R=--NR¹ R²

and R¹ =hydrogen,

R² =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or2-methylpropyl;

and when R¹ =methyl or ethyl,

R² =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or2-methylpropyl;

R³ is selected from hydrogen; straight or branched (C₁ -C₈)alkyl groupselected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl, heptyl and octyl; α-hydroxy(C₁ -C₄)alkyl group selected fromhydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl, α-hydroxypropyland α-hydroxybutyl; carboxyl(C₁ -C₈)alkyl group; (C₆ -C₁₀)aryl groupselected from phenyl, α-naphthyl and β-naphthyl; substituted(C₆-C₁₀)aryl group (substitution selected from hydroxy, halogen, (C₁-C₄)alkoxy, (C₁ -C₄)alkoxycarbonyl, and carboxy); (C₇ -C₉)aralkyl groupselected from benzyl, 1-phenylethyl, 2-phenylethyl and phenylpropyl;substituted(C₇ -C₉)aralkyl group [substitution selected from halo, (C₁-C₄)alkyl, (C₁ -C₄)alkoxy, (C₁ -C₄)alkylsulfonyl, cyano and carboxy];

R⁴ is selected from hydrogen and (C₁ -C₄)alkyl selected from methyl,ethyl propyl, isopropyl, butyl and isobutyl;

when R³ does not equal R⁴ the stereochemistry of the asymmetric carbon(i.e., the carbon bearing the W substituent) maybe be either theracemate (DL) or the individual enantiomers (L or D); and thepharmacologically acceptible organic and inorganic salts or metalcomplexes.

Particularly preferred compounds are compounds according to the aboveformula III wherein:

Y is selected from (CH₂)_(n) X', n=0-5, X' is halogen selected frombromine, chlorine, fluorine and iodine;

X is halogen or trifluoromethanesulfonyloxy, the halogen is selectedfrom bromine, chlorine, fluorine and iodine;

R is selected from hydrogen; halogen selected from bromine, chlorine andiodine; or R=--NR¹ R²

and when R=--NR¹ R² and R¹ =hydrogen,

R² =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl,2-methylpropyl or 1,1-dimethylethyl;

and when R¹ =methyl or ethyl,

R² =methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or2-methylpropyl;

R³ is selected from hydrogen; straight or branched (C₁ -C₆)alkyl groupselected from methyl, ethyl, propyl, isopropyl, butyl, .isobutyl, pentyland hexyl; (C₆ -C₁₀)aryl group selected from phenyl, α-naphthyl andβ-naphthyl; (C₇ -C₉)aralkyl group selected from benzyl, 1-phenylethyl,2-phenylethyl and phenylpropyl; R⁴ is selected from hydrogen and (C₁-C₄)alkyl selected from methyl, ethyl propyl, isopropyl, butyl andisobutyl; when R³ does not equal R⁴ the stereochemistry of theasymmetric carbon (i.e., the carbon bearing the W substituent) maybe beeither the racemate (DL) or the individual enantiomers (L or D); and thepharmacologically acceptible organic and inorganic salts or metalcomplexes.

Compounds of special interest are compounds according to the aboveformula III wherein:

Y is selected from (CH₂)_(n) X', n=0-5, X' is halogen selected frombromine, chlorine, flourine and iodine;

X is halogen or trifluoromethanesulfonyloxy, the halogen is selectedfrom chlorine and fluorine; R is selected from hydrogen; halogenselected from chlorine and iodine;

or R=--NR¹ R²

and when R=--NR¹ R²

and R¹ =methyl or ethyl,

R² =methyl and ethyl;

R³ is selected from hydrogen; straight or branched (C₁ -C₂)alkyl groupselected from methyl and ethyl;

R⁴ is selected from hydrogen and (C₁ -C₆)alkyl selected from methyl andethyl;

when R³ does not equal R⁴ the stereochemistry of the asymmetric carbon(i.e., the carbon bearing the W substituent) maybe be either theracemate (DL) or the individual enantiomers (L or D); and thepharmacologically acceptible organic and inorganic salts or metalcomplexes.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The novel compounds of the present invention may be readily prepared inaccordance with the following schemes. ##STR20##

    R=NR.sup.2 N.sup.3, R.sup.2 =R.sup.3                       (1a.)

    R=NR.sup.2 R.sup.3, R.sup.2 ≠R.sup.3                 (1b.)

    R=X, X=halogen, hydrogen                                   (1c.)

The starting 9-azido-7-(substituted)-6-demethyl-6-deoxytetracycline, 1,described in formula 1 is prepared according to Scheme I. ##STR21##

In accordance with Scheme I,9-amino-7-(substituted)-6-demethyl-6-deoxytetracycline 2, or the mineralacid or halide salt, dissolved in 0.1N methanolic hydrogen chloride, istreated for from 5 minutes to 8 hours at from -20° C. to +45° C. with anexcess of n-butyl nitrite to give a9-diazonium-7-(substituted)-6-demethyl-6-deoxytetracycline, 3, or themineral acid or halide salt. The formed diazonium compound, 3, or themineral acid or halide salt, dissolved in 0.1N methanolic hydrogenchloride, is treated for 5 minutes to 8 hours at from -5° C. to +50° C.with one equivalent of sodium azide to give the corresponding9-azido-7-(substituted)-6-demethyl-6-deoxytetracycline, 1, or themineral acid or halide salt. ##STR22##

In accordance with Scheme II, a9-azido-7-(substituted)-6-demethyl-6-deoxytetracycline, 1, or themineral acid or halide salt, is treated for from 5 minutes to 12 hoursat from -5° C. to 40° C. with a strong acid, such as sulfuric acid,hydrochloric acid, methanesulfonic acid, trifluoromethanesulfonic acid,hydrobromic, hydroiodic, or hydrogen fluoride to produce a9-amino-7-(substituted)-8-(substituted)-6-demethyl-6-deoxytetracycline,4, or the mineral acid or halide salt.

The9-amino-7-(substituted)-8-(substituted)-6-demethyl-6-deoxytetracycline,4, or the mineral acid or halide salt, can be further converted asdescribed in Scheme III. ##STR23##

In accordance with Scheme III, a9-amino-7-(substituted)-8-(substituted)-6-demethyl-6-deoxytetracycline,4, or the mineral acid or halide salt, is treated at room temperaturefor from 0.5-2 hours with an acid chloride of the formula: ##STR24##wherein R³, R⁴ W and X are defined hereinabove; in the presence of asuitable acid scavenger, in a suitable solvent, to form thecorresponding 9-[(substitutedglycyl)amido]-7-(substituted)-8-(substituted)-6-demethyl-6-deoxytetracycline,5, or the mineral acid or halide salt.

The acid scavenger is selected from sodium bicarbonate, sodium acetate,pyridine, triethylamine, N, O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, potassium carbonate, a basic ionexchange resin or equivalent thereof.

The solvents are selected from water, tetrahydrofuran,N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone,hexamethylphosphoramide,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone, 1,2-dimethoxyethaneor equivalent thereof.

Alternatively, in accordance with Scheme III,9-amino-7-(substituted)-8-(substituted)-6-demethyl-6-deoxytetracycline,4, or the mineral acid or halide salt, is treated with a straight orbranched chain α-haloacyl halide of the formula: ##STR25## wherein R³,R⁴ and Y are defined hereinabove and Q is halogen selected from bromine,chlorine, fluorine and iodine, such as bromoacetyl bromide, chloroacetylchloride, 2-bromopropionyl bromide or equivalent thereof; in thepresence of a suitable acid scavenger, in a suitable of solvent, to formthe corresponding9-[(haloacyl)amido]-7-(substituted)-8-(substituted)-6-demethyl-6-deoxytetracycline,6, or the mineral acid or halide salt.

The halogen, Y, and halide, Q, in the haloacyl halide can be the same ordifferent halogen and are selected from bromine, chlorine, iodine andfluorine; Y is (CH₂)_(n) X', n=0-5 and X' is a halogen.

The acid scavenger and suitable solvent are as defined hereinabove.

The9-[(haloacyl)amido]-7-(substituted)-8-(substituted)-6-demethyl-6-deoxytetracycline,6, or mineral acid or halide salt, is treated, under an inert atmosphereof nitrogen, argon or helium, with nucleophiles of the formula, WH,where W is defined hereinabove, such as amines or substituted amines orequivalents thereof, in a suitable solvent to form the corresponding9-[(substitutedglycyl)amido]-7-(substituted)-8-(substituted)-6-demethyl-6-deoxytetracycline,5, or mineral acid or halide salt. ##STR26##

In accordance with Scheme IV, compound 5 is selectively N-alkylated inthe presence of formaldehyde and either a primary amine of the formulaR⁵ NH₂ such as methylamine, ethylamine, benzylamine, methyl glycinate,(L or D) lysine, (L or D)alanine or their substituted congeners; or asecondary amine of the formula R⁵ R⁶ NH such as morpholine, pyrrolidine,piperidine or their substituted congeners to give the correspondingMannich base adduct, 7.

The 9-[(substitutedglycyl)amido]-7-(substituted)-8-(substituted)-6-demethyl-6-deoxytetracyclinesmay be obtained as metal complexes such as aluminum, calcium, iron,magnesium, manganese and complex salts; inorganic and organic salts andcorresponding Mannich base adducts using methods known to those skilledin the art (Richard C. Larock, Comprehensive Organic Transformations,VCH Publishers, 411-415, 1989). Preferably, the7-(substituted)-8-(substituted)-9-(substituted)-6-demethyl-6-deoxytetracyclinesare obtained as inorganic salts such as hydrochloric, hydrobromic,hydroiodic, phosphoric, nitric or sulfate; or organic salts such asacetate, benzoate, citrate, cysteine or other amino acids, fumarate,glycolate, maleate, succinate, tartrate, alkylsulfonate orarylsulfonate. Depending on the stoichiometry of the acids used, thesalt formation occurs with the C(4)-dimethylamino group (1 equivalent ofacid ) or with both the C(4)-dimethylamino or the W group (2 equivalentsof acid). The salts are preferred for oral and parenteraladministration.

Some of the compounds of the hereinbefore described Schemes have centersof asymmetry at the carbon bearing the W substituent. The compounds may,therefore, exist in at least two (2) stereoisomeric forms. The presentinvention encompasses all stereoisomers of the compounds whether freefrom other stereoisomers or admixed with stereoisomers in any proportionof enantiomers. The absolute configuration of any compound may bedetermined by conventional X-ray crystallography.

The stereochemistry centers on the tetracycline unit (i.e., C-4, C-4a,C-5a and C-12a) remain intact throughout the reaction sequences.

BIOLOGICAL ACTIVITY

Methods for in Vitro antibacterial evaluation

(Table I)

The minimum inhibitory concentration (MIC), the lowest concentration ofthe antibiotic which inhibits growth of the test organism, is determinedby the agar dilution method using 0.1 ml Muller-Hinton II agar(Baltimore Biological Laboratories) per well. An inoculum level of1-5×10⁵ CFJ/ml, and a range of antibiotic concentrations (32-0.004microgram/ml) is used. MIC is determined after the plates are incubatedfor 18 hours at 35° C. in a forced air incubator. The test organismscomprise genetically defined strains that are sensitive to tetracyclineand resistant strains that are insensitive to tetracycline, either bypreventing the antibiotic from interacting with bacterial ribosomes(tetM) or by a tetK encoded membrane protein which confers tetracyclineresistance by energy-dependent efflux of the antibiotic from the cell.

Testing Results

The claimed compounds exhibit antibacterial activity against a spectrumof tetracycline sensitive and resistant Gram-positive and Gram-negativebacteria, especially, strains of E. coli, S. aureus and E. faecalis,containing the tetM resistance determinants (Table I). Notable is8-chloro-9-(N,N-dimethylglycyl-amido)- 6-demethyl-6-deoxytetracycline,as shown in Table I, which has good in vitro activity againsttetracycline resistant strains containing the tetM resistancedeterminant (such as S. aureus UBMS 88-5, S. aureus UBMS 90-1 and 90-2,E. coli UBMS 89-1 and 90-4) and is equally as effective as minocyclineagainst susceptible strains.

Most importantly, these compounds also exhibit antibacterial activityagainst bacteria that contain an active efflux resistant mechanism as intetA, tetB, or tetK (i.e., E. coli UBMS 88-1, E. coli PRPI tetA, E. coliMe4100 TN10-tetB, and S. aureus UBMS 88-7 tetK).

As can be seen from Table I, compounds of the invention may be used toprevent or control important mammalian and veterinary diseases such asdiarrhea, urinary tract infections, infections of skin and skinstructure, ear, nose and throat infections, wound infections, mastitisand the like.

COMPOUND LEGEND FOR TABLES

A

[4S-(4α,12aα)]-8-Chloro-4-(dimethylamino)-9-[[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidedisulfate.

B

[4S-(4α,12aα)]-8-Chloro-4,7-(dimethylamino)-9-[[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.

C

[4S-(4α,12aα)]-8-Chloro-4-(dimethylamino)-9-[[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.

D

[4S-(4α,12aα)]-9-[[(Butylaminoacetyl]amino]-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidedihydrochloride.

E

[7S-(7α,10aα)]-N-[9-(Aminocarbonyl)-3-chloro-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-1-pyrrolidineacetamidedihydrochloride.

F

[4S-(4α,12aα)]-8-Chloro-4-(dimethylamino)-1,4,-4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetra-hydroxy-1,11-dioxo-9-[[(propylamino)acetyl]amino]-2-naphthacenecarboxamidedihydrochloride.

G

[4S-(4α,12aα)]-8-Chloro-9-[[(cyclopropylmethylamino)acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidedihydrochloride.

H

[4S-(4α,12aα)]-8-Chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[(pentylamino)acetyl]amino]-2-naphthacenecarboxamidedihydrochloride.

I

[4S-(4α,12aα)]-8-Chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[(methylamino)acetyl]amino]-2-naphthacenecarboxamidedihydrochloride.

J

[7S-(7α,10aα)]-N-[9-(Aminocarbonyl)-3-chloro-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-1-piperidineacetamidedihydrochloride.

K

[4S-(4α,12aα)]-9-[(Chloroacetyl)amino]-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrochloride.

L

Minocycline

M

Tetracycline

                                      TABLE I                                     __________________________________________________________________________    ANTIBACTERIAL ACTIVITY OF                                                     8-(SUBSTITUTED)-9-[(SUBSTITUTED GLYCYL)AMIDO]-6-DEMETHYL-6-DEOXYTETRACYCLI    NES                                                                           MIC (ug/ml)                                                                                  Compound                                                       Organism       A  B  C  D  E  F  G  H  I  J  K  L  M                          __________________________________________________________________________    E. coli UBMS 88-1 Tet B                                                                      2  >32                                                                              1  2  1  0.5                                                                              1  2  1  4  >32                                                                              16 >32                        E. coli J3272 Tet sens                                                                       1  NT NT NT NT NT NT NT NT NT NT NT NT                         E. coli MC 4100 Tet sens.                                                                    NT 2  0.25                                                                             0.25                                                                             0.25                                                                             0.12                                                                             0.25                                                                             0.25                                                                             0.25                                                                             1  8  0.25                                                                             0.5                        E. coli PRP1 Tet A                                                                           4  16 8  4  2  4  4  2  16 8  >32                                                                              4  32                         E. coli MC 4100 TNIOC Tet B                                                                  2  >32                                                                              1  1  1  0.5                                                                              1  2  1  4  >32                                                                              8  >32                        E. coil J3272 Tet C                                                                          8  16 8  2  1  1  1  2  16 4  >32                                                                              2  >32                        E. coli UBMS 89-1 Tet M                                                                      0.5                                                                              32 0.25                                                                             0.5                                                                              0.25                                                                             0.5                                                                              0.5                                                                              0.5                                                                              2  1  8  16 32                         E. coll UBMS 89-2 Tet sens.                                                                  2  16 1  2  1  1  1  2  2  4  >32                                                                              1  2                          E. coil J2175  1  32 1  1  1  1  1  2  1  4  >32                                                                              1  2                          E. coli BAJ9003 IMP MUT                                                                      0.25                                                                             0.12                                                                             0.12                                                                             0.25                                                                             0.12                                                                             0.12                                                                             0.12                                                                             0.25                                                                             0.25                                                                             0.25                                                                             1  0.06                                                                             0.5                        E. coli UBMS 90-4 Tet                                                                        1  >32                                                                              0.5                                                                              1  1  0.5                                                                              1  2  1  4  >32                                                                              >32                                                                              32                         E. coli UBMS 90-5                                                                            1  32 1  1  1  0.5                                                                              1  2  1  4  >32                                                                              1  1                          E. coli #311 (MP)                                                                            0.5                                                                              4  0.5                                                                              1  0.25                                                                             0.5                                                                              1  2  2  2  16 1  1                          E. coli ATCC 25922                                                                           0.5                                                                              8  0.5                                                                              1  0.25                                                                             0.5                                                                              1  2  1  2  16 1  1                          E. coli J3272 Tet D                                                                          0.5                                                                              32 0.5                                                                              1  0.25                                                                             0.25                                                                             1  1  1  2  >32                                                                              8  >32                        S. mariescens FPOR 8733                                                                      16 >32                                                                              8  16 8  8  8  16 16 >32                                                                              >32                                                                              8  >32                        X. maltophilia NEMC 87210                                                                    2  0.5                                                                              0.05                                                                             4  1  2  4  4  16 4  8  0.25                                                                             8                          Ps. acruginosa ATCC 27853                                                                    >32                                                                              >32                                                                              >32                                                                              >32                                                                              32 32 32 >32                                                                              16 >32                                                                              >32                                                                              8  16                         S. aureus NEMC 8769                                                                          0.06                                                                             0.12                                                                             0.03                                                                             0.5                                                                              0.25                                                                             0.25                                                                             0.5                                                                              0.5                                                                              0.5                                                                              0.5                                                                              0.5                                                                              0.12                                                                             0.25                       S. aureus UBMS 88-4                                                                          0.12                                                                             0.25                                                                             0.12                                                                             0.5                                                                              0.25                                                                             0.25                                                                             0.5                                                                              0.5                                                                              0.5                                                                              1  0.5                                                                              0.12                                                                             0.25                       S. aureus UBMS 88-5 Tet N                                                                    0.25                                                                             0.25                                                                             2  1  0.25                                                                             0.5                                                                              0.5                                                                              1  0.5                                                                              1  1  8  >32                        S. aureus UBMS 88-7 Tet K                                                                    2  2  0.25                                                                             8  2  8  8  4  32 >2 4  0.25                                                                             >32                        S. aureus UBMS 90-1 Tet M                                                                    0.5                                                                              0.5                                                                              4  2  0.25                                                                             0.5                                                                              2  2  0.5                                                                              2  1  8  >32                        S. aureus UBMS 90-3                                                                          0.12                                                                             0.12                                                                             0.12                                                                             0.12                                                                             0.12                                                                             0.5                                                                              0.12                                                                             0.25                                                                             0.5                                                                              0.25                                                                             0.25                                                                             0.06                                                                             0.25                       S. aureus UBMS 90-2 Tet M                                                                    0.5                                                                              0.25                                                                             1  0.5                                                                              0.25                                                                             0.25                                                                             0.5                                                                              0.25                                                                             0.5                                                                              0.5                                                                              0.5                                                                              4  32                         S. aureus IVES 2943                                                                          4  4  4  16 4  16 16 8  >32                                                                              2  4  4  >32                        S. aureus ROSE (MP)                                                                          16 8  1  16 8  16 32 8  >32                                                                              4  4  1  >32                        S. aureus SMITH (MP)                                                                         0.25                                                                             0.12                                                                             0.12                                                                             0.5                                                                              0.25                                                                             0.25                                                                             0.5                                                                              0.5                                                                              0.5                                                                              1  0.5                                                                              0.12                                                                             0.25                       S. aureus IVES 1 983                                                                         4  4  4  8  4  8  16 4  >32                                                                              4  4  4  >32                        S. aureus A7CC 29213                                                                         0.03                                                                             0.25                                                                             0.25                                                                             0.5                                                                              0.25                                                                             0.25                                                                             0.25                                                                             0.5                                                                              0.5                                                                              0.5                                                                              0.5                                                                              0.12                                                                             0.25                       S. hemolyticus AVHAH 88-3                                                                    1  0.5                                                                              0.5                                                                              8  2  4  8  4  2  4  4  0.25                                                                             1                          Enterococcus 12201                                                                           0.25                                                                             0.12                                                                             8  0.5                                                                              0.25                                                                             0.25                                                                             0.25                                                                             0.25                                                                             0.5                                                                              0.5                                                                              2  8  >32                        E. faecalls ATCC 29212                                                                       0.12                                                                             0.12                                                                             0.5                                                                              0.25                                                                             0.12                                                                             0.12                                                                             0.25                                                                             0.12                                                                             0.25                                                                             0.25                                                                             0.5                                                                              4  16                         __________________________________________________________________________

When the compounds are employed as anti-bacterials, they can be combinedwith one or more pharmaceutically acceptable carriers, for example,solvents, diluents and the like, and may be administered orally in suchforms as tablets, capsules, dispersible powders, granules, orsuspensions containing, for example, from about 0.05 to 5% of suspendingagent, syrups containing, for example, from about 10 to 50% of sugar,and elixirs containing for example, from about 20 to 50% ethanol and thelike, or parenterally in the form of sterile injectable solutions orsuspensions containing from about 0.05 to 5% suspending agent in anisotonic medium. Such pharmaceutical preparations may contain, forexample, from about 25 to about 90% of the active ingredient incombination with the carrier, more usually between about 5% and 60% byweight.

An effective amount of compound from 2.0 mg/kg of body weight to 100.0mg/kg of body weight should be administered one to five times per dayvia any typical route of administration including but not limited tooral, parenteral (including subcutaneous, intravenous, intramuscular,intrasternal injection or infusion techniques), topical or rectal, indosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. It will beunderstood, however, that the specific dose level and frequency ofdosage for any particular patient may be varied and will depend upon avariety of factors including the activity of the specific compoundemployed, the metabolic stability and length of action of that compound,the age, body weight, general health, sex, diet, mode and time ofadministration, rate of excretion, drug combination, the severity of theparticular condition, and the host undergoing therapy.

These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvants customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease ofpreparation and administration are solid compositions, particularlytablets and hard-filled or liquid-filled capsules. Oral administrationof the compounds is preferred.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inglycerol, liquid, polyethylene glycols and mixtures thereof in oils.Under ordinary conditions of storage and use, these preparations containa preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserve against thecontaminating action of microorganisms such as bacterial and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oil.

The invention will be more fully described in conjunction with thefollowing specific examples which are not be construed as limiting thescope of the invention.

EXAMPLE 1 [7S-(7alpha,10alpha)]-9-(Aminocarbonyl)-4,7-bis(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenediazoniumchloride sulfate (1:1)

To a 0° C. solution of 3.0 g of9-amino-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide sulfate,dissolved in 100 ml of 0.1N methanolic hydrogen chloride is added,dropwise, 6.6 ml of butyl nitrite. The reaction is stirred at 0° C. for1 hour, poured into 400 ml of diethyl ether, collected and dried to give2.64 g of the desired product.

MS(FAB): m/z 484 (M+H)

EXAMPLE 2 [4S-(4α,12aα]-9-Azido-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11,dioxo-2-naphthacenecarboxamidehydrochloride (1:1)

To a room temperature solution of 2.64 g of product from Example 1dissolved in 84 ml of 0.1N methanolic hydrogen chloride is added 0.353 gof sodium azide. The mixture is stirred at room temperature for 4 hours,poured into 500 ml of diethyl ether and collected to give 2.5 g of thedesired product.

IR(KBr): 2080 cm⁻¹.

EXAMPLE 39-Amino-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideSulfate

One gram of product from Example 2 is added to 10 ml of 0° C.concentrated sulfuric acid. The reaction is stirred at 0° C. for 1.5hours, poured into 500 ml of diethyl ether, collected and dried to give1.1 g of the desired product.

MS(FAB): m/z 507 (M+H).

EXAMPLE 4 4S-(4α,12aα)]-9-Amino-4,7-bis(dimethylamino)-8-fluoro-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The title compound is prepared by the procedure of Example 3 using theproduct of Example 2 and liquid hydrogen fluoride.

EXAMPLE 59-Amino-8-chloro-4-(dimethylamino)-4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrochloride (1:1)

To 10 ml of concentrated hydrochloric acid at 0° C. is added 0.20 g of9-azido-6-demethyl-6-deoxytetracycline hydrochloride prepared by theprocedure described in J. Am. Chem. Soc., 84: 1426-1430. The reaction isstirred at 0° C. for 11/2hours and concentrated in vacuo to give 0.195 gof the desired product.

MS(FAB): m/z 464 (M+H).

EXAMPLE 6 4S-(4α,12aα)]-9-Amino-4,7-bis(dimethylamino)-8-fluoro-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The title compound is prepared by the procedure of Example 3 using9-azido-6-demethyl-6-deoxytetracycline and liquid hydrogen fluoride.

EXAMPLE 7[4S-(4α,12aα)]-9-Amino-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-8-[[(trifluoromethyl)-sulfonyl]oxy]-2-naphthacenecarboxamide

The title compound is prepared by the procedure of Example 3 using9-azido-4,7-bis(dimethylamino)-6-demethyl-6-deoxytetracycline andtrifluoromethanesulfonic acid

EXAMPLE 8[4S-(4α,12aα)]-9-Amino-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a,tetrahydroxy-1,11-dioxo-8-[[(trifluoromethyl)sulfonyl]oxy]-2-naphthacenecarboxamide

The title compound is prepared by the procedure of Example 3 using9-azido-4-(dimethylamino)-6-demethyl-6-deoxytetracycline andtrifluoromethanesulfonic acid.

EXAMPLE 9[4S-(4α,12aα)]-9-[(Chloroacetyl)amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

A well-stirred cold solution of 1.0 g of product from Example 3, 2 ml of1,3-dimethyl-2-imidazolidinone and 1.0 g of sodium bicarbonate istreated with 0.30 ml of chloroacetyl chloride. The solution is stirredat 25° C. for 30 minutes, filtered and the filtrate added dropwise to500 ml of diethyl ether to afford 1.0 g of yellow product.

EXAMPLE 10[4S-(4α,12aα)]-9-[(Bromoacetyl)amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

A well-stirred cold solution of 1.0 g of product from Example 3, 2 ml of1,3-dimethyl-2-imidazolidinone and 1.0 g of sodium bicarbonate wastreated with 0.36 ml of bromoacetyl bromide. The solution was stirred at25° C. for 30 minutes, filtered and the filtrate added dropwise to 500ml of diethyl ether to afford 0.7 g of yellow product.

EXAMPLE 11[4S-(4α,12aα)]-9-[(α-Bromopropionyl)amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

A well-stirred cold solution of 1.0 g of product from Example 3, 2 ml of1,3-dimethyl-2-imidazolidinone and 1.0 g of sodium bicarbonate wastreated with 0.42 ml of bromopropionyl bromide. The solution was stirredat 25° C. for 30 minutes, filtered and the filtrate added dropwise to500 ml of diethyl ether to afford 1.0 g of yellow product.

Substantially following the method, described in detail herein above inExample 10, the compounds of the invention listed in Examples 12-19 areprepared.

EXAMPLE 12[4S-(4α,12aα)]-9-[(Bromocyclobutylacetyl)amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideExample 13[4S-(4α,12aα)]-9-[(Bromophenylacetyl)amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 14[4S-(4α,12aα)]-9-[(α-Bromo-α-cyclopropylpropionyl)amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 15[4S-(4α,12aα)]-9-[(α-Bromo-2,2-dimethylbutyryl)amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 16[4S-(4α,12aα)]-9-[(α-Bromo-(2,4-difluorophenyl)acetyl)amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 17[4S-(4α,12aα)]-9-[(α-Bromo-(2-furylpropionyl)amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 18[4S-(4α,12aα)]-9-[(α-Bromo-(3-methoxycarbonylpropionyl))amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 19[4S-(4α,12aα)]-9-[(α-Bromo-(4-methoxycarbonylbutyryl))amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 20 [4S-(4α,12aα)]-9-[(Bromoacetyl)amino]-8-fluoro-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The title compound is prepared by the procedure of Example 10 using theproduct from Example 4.

EXAMPLE 21[4S-(4α,12aα)]-9-[(Bromoacetyl)amino]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-8-[[(trifluoromethyl)sulfonyl]oxy]-2-naphthacenecarboxamide

The title compound is prepared by the procedure of Example 10 and usingthe product from Example 7.

EXAMPLE 22[4S-(4α,12aα)]-9-[(Chloroacetyl)amino]-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrochloride

A 25° C. solution of 1.247 g of product from Example 5, 12 ml of DMPUand 6 ml of acetonitrile is treated with 0.564 g of chloroacetylchloride. The mixture is stirred for 45 minutes and added dropwise to amixture of 80 ml of 2-propanol and 400 ml of diethyl ether. Theresultant yellow solid is filtered and washed several times with diethylether and dried in vacuo to give 1.25 g of product.

MS(FAB)=m/z 540(M+H)

EXAMPLE 23[4S-(4α,12aα)]-9-[(Bromoacetyl)amino]-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrochloride

A 25° C. solution of 1.247 g of product from Example 5, 12 ml of DMPUand 6 ml of acetonitrile is treated with 0.62 g of bromoacetyl bromide.The mixture is stirred for 45 minutes and added dropwise to a mixture of80 ml of 2-propanol and 400 ml of diethyl ether. The resultant yellowsolid is filtered and washed several times with diethyl ether and driedin vacuo to give 1.35 g of product.

Substantially following the method, described in-detail herein above inExample 22 or 23, the compounds of the invention listed in Examples24-30 are prepared.

EXAMPLE 24[4S-(4α,12aα)]-9-[(Chloropropionyl)amino]-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrochloride EXAMPLE 25[4S-(4α,12aα)]-9-[(Chlorobutyryl)amino]-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrochloride EXAMPLE 26[4S-(4α,12aα)]-9-[[(4-Hydroxyphenyl)-α-chloroacetyl]amino]-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrochloride EXAMPLE 27[4S-(4α,12aα)]-9-[[(2-Fluorophenyl)-α-bromoacetyl[amino[-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrobromide EXAMPLE 28[4S-(4α,12aα)]-9-[(2-Bromo-4-pentenoyl)amino]-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide hydrobromide EXAMPLE 29[4S-(4α,12aα)]-9-[(α-Bromophenylbutyryl)amino]-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrobromide EXAMPLE 30[4S-(4α,12aα)]-9-[((4-Pyridyl)-α-bromoacetyl)amino]-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidehydrobromide EXAMPLE 31[4S-(4α,12aα)]-9-[(Bromoacetyl)amino]-4-chloro-4-(dimethylamino)-8-fluoro-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The title compound is prepared by the procedure of Example 10 using theproduct from Example 6.

EXAMPLE 32[4S-(4α,12aα)]-9-[(Bromoacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-8[[(trifluoromethyl)sulfonyl]oxy]-2-naphthacenecarboxamide

The title compound is prepared by the procedure of Example 10 using theproduct from Example 8.

EXAMPLE 33[4S-(4α,12aα)]-8-Chloro-4-(dimethylamino)-9-[[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidedisulfate

A well stirred solution (25° C.) of 0.2805 g of product from Example 5,10 ml of DMPU, 3 ml of acetonitrile and 0.3 g of sodium carbonate istreated with 0.157g of N,N-dimethylaminoacetyl chloride hydrochloride.After 30 minutes, the reaction is filtered and the filtrate is addeddropwise to 300 ml of diethyl ether. Concentrated sulfuric acid is addeddropwise and a yellow solid precipitated. The yellow solid is collected,washed well with ether, and dried in vacuo to afford 0.21 g of product:

MS(FAB)=m/z 549(M+H).

EXAMPLE 34[4S-(4α,12aα)]-8-Chloro-4-(dimethylamino)-9-[[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

A well stirred solution 25° C. of 0.20 g of product from Example 5, 3 mlof N-methylpyrrolidone, 1 ml of acetonitrile and 0.2 g of sodiumbicarbonate is treated with 0.071 g of N,N-dimethylaminoacetyl chloridehydrochloride. After 30 minutes, the reaction is filtered and thefiltrate is added dropwise to 200 ml of diethyl ether. The yellow solidis collected, washed well with ether, and dried in vacuo to afford 0.15g of product:

MS(FAB)=m/z 548(M+H) .

EXAMPLE 35[4S-(4α,12aα)]-8-Chloro-4,7-(dimethylamino)-9-[[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

A well stirred solution (25° C.) of 0.104 g of product from Example 3,1.5 ml of N-methylpyrrolidone, 0.5 ml of acetonitrile and 0.105 g ofsodium bicarbonate is treated with 0.034 g of N,N-dimethylaminoacetylchloride hydrochloride. After 1 hr, the reaction is filtered and thefiltrate is added dropwise to 100 ml of diethyl ether. The yellow solidis collected, washed well with ether, and dried in vacuo to afford 0.085g of product:

MS(FAB)=m/z 591(M+H).

EXAMPLE 36[4S-(4α,12aα)]-9-[[(Butylamino)acetyl]amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

A solution of 0.20 g of the product from Example 10, 2 ml of1,3-dimethyl-2-imidazolidinone and 0.1 ml of n-butylamine is stirred atroom temperature for 1 hr and added dropwise to 50 ml of diethyl etherto afford 0.20 g of yellow color product:

MS (FAB) m/z 620 (M+H)

Substantially following the method, described in detail herein above inExample 36, the compounds of the invention listed in Examples 37-45 areprepared.

EXAMPLE 37[4S-(4α,12aα)]-8-Chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12,12a-octahydro-3,10,12a-tetrahydroxy-9-[[[(3-methylcyclobutyl)amino]acetyl]-amino]-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 38[7S-(7α,10aα)]-N-[9-(Aminocarbonyl)-3-chloro-4,7bis(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy,10,12-dioxo-2-naphthacenyl]-1H-pyrrole-1-acetamideEXAMPLE 39[7S-(7a,10aα)]-N-[9-(Aminocarbonyl)-3-chloro-4,7-bis(dimethlamino)-5,5a,6,6a,7,10,10a12-octahydro-1,8,10a,11-tetrahydroxy,-10,12-dioxo-2-naphthacenyl]-1H-pyrrole-1-acetamideEXAMPLE 40 [4S-(4a,12aα)]-8-Chloro-4,7-bis(dimethylamino)-9-[[[(1,1-dimethylethyl)amino]acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 41[4S-(4α,12aα)]-8-Chloro-9-[[(cyclopropylamino)acetyl]-amino]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 42[4S-(4α,12aα)]-8-Chloro-9-[[[(cyclobutyloxy)amino]-acetyl]amino]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,-11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxmideEXAMPLE 43[7S-(7α,10aα)]-N](Aminocarbonyl)-3-chloro-4,7-bis(dimethlamino)-5,5a,6,6a7,10,10a,12-octahydro-1,8,10a11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-1pyrrolidineacetamideEXAMPLE 44[7S-(7α,10aα)]-N-[9-(Aminocarbonyl)-3-chloro-4,7-bis-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,89,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-(3-methyl-1-pyrrolidine)acetamideEXAMPLE 45[4S-(4α,12aα)]-8-Chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-9-[[[(propylamino)]-acetyl]amino]-2-naphthacenecarboxamideEXAMPLE 46[4S-(4α12aα)]-8-Chloro-4,7-bis(dimethylamino)-1,4,-4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[1-oxo-2-(propylamino)propyl]amino]-2-naphthacenecarboxamine

The title compound is prepared by the procedure of Example 36 using[4S-(4α,12aα)]-9-[(α-bromopropionyl)amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetra-hydroxy-1,11-dioxo-2-naphthacenecarboxamideand n-propylamine.

EXAMPLE 47[7S-(7α,10aα)]-N-[9-(Aminocarbonyl)-3-chloro-4,7-bis(dimethylamino)-5,5a,6,6a,7,10,10a,12a-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-α-cyclobutyltetrahydro-2H-1,2-isoxazine-2-acetamide

The title compound is prepared by the procedure of Example 36 using[4S-(4α,12aα)]-9-[(α-bromocyclobutylacetyl)amino]-8-chloro-4,7-bis-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,-12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide andtetrahydro-1,2-oxazine.

EXAMPLE 48[4S-(4α12,12aα)]-8-Chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[phenyl[(phenyl-methyl)amino]acetyl]amino]-2-naphthacenecarboxamide

The title compound is prepared by the procedure of Example 36 using[4S-(4α,12aα)]-9-[(α-bromophenylacetyl)amino]-8-chloro-4,7-bis(dimethyl-amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideand benzylamine.

EXAMPLE 49[7S-(7α,10aα)]-N-[9-(Aminocarbonyl)-3-chloro-4,7-bis-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,-10a,11-tetrahydroxy-10,12-dioxo-2-napthacenyl]-α-cyclopropyl-α-methyl-1-azetidineacetamide

The title compound is prepared by the procedure of Example 36 using[4S-(4α,12aα)]-9-[(α-bromo-α-cyclopropylproprionyl)amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-napthacenecarboxamideand azetidine.

EXAMPLE 50[7S-(7α,10aα)]-N-[9-(Aminocarbonyl)-3-chloro-4,7-bis-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-α-(1,1-dimethylethyl)-3-methyl-4-morpholine)acetamide

The title compound is prepared by the procedure of Example 36 using[4S-(4α,12aα)]-9-[(α-bromo-2,2-dimethylbutyryl)amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,-12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideand 3-methyl-4-morpholine.

EXAMPLE 51[4S-(4α,12aα)]-8-Chloro-9-[[(2,4-difluorophenyl)[(2-phenylethyl)amino]acetyl]amino]-4,7-bis(dimethyl-amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The title compound is prepared by the procedure Example 36 using[4S-(4α,12aα)]-]9-(α-bromo-(2,4-difluorophenyl)acetyl)amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,-12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideand 2-phenethylamine.

EXAMPLE 52[7S-(7α,10aα)]-N-[9-(Aminocarbonyl)-3-chloro-4,7-bis(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-α-(methoxyamino)-α-methyl-2-furanacetamide

The title compound is prepared by the procedure of Example 36 using[4S-(4α,12aα)]-9-[(α-bromo-(2-furyl)propionyl))amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,-12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideand methoxyamine.

Substantially following the method, described in detail herein above inExample 36, the compounds of the invention listed in Examples 53-54 areprepared from[4S-(4α,12aα)]-9[(α-bromo-(3-methoxycarbonylpropionly))amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.

EXAMPLE 53[7S-(7α,10aα)]-4-[[9-(Aminocarbonyl)-3-chloro-4,7-bis(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-amino-3,-[(1,1-dimethylethyl)amino]-4-oxobutanoicacid methyl ester EXAMPLE 54[7S-(7α,10aα)]-4-[[9-(Aminocarbonyl)-3-chloro-4,7-bis(dimethylamino-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-amino]-3-(dimethylamino)-4-oxobutanoicacid methyl ester EXAMPLE 55[7S-(7α,10aα)]-λ-[[[9-(Aminocarbonyl)-3-chloro-4,7-bis(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-amino]carbonyl]-1-pyrrolidinebutanoicacid methyl ester

The title compound is prepared by the procedure of Example 36 using[4S-(4α,12aα)]-9-[(α-bromo-(4-methoxycarbonylbutyryl))amino]-8-chloro-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,-10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideand pyrrolidine.

EXAMPLE 56[4S-(4α,12aα)]-4,7-Bis(Dimethylamino)-9-[[(dimethyl-amino)acetyl]amino]-8-fluoro-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The title compound is prepared by the procedure of Example 36 using[4S-(4α,12aα)]-9-[(bromo-acetyl)amino]-4,7-bis(dimethylamino)-8-fluro-1,4,4a,-5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideand dimethylamine.

EXAMPLE 57[4S-(4α,12aα)]-9-[[(Butylamino)acetyl]amino]-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidedihydrochloride

A mixture of 0.20 g of the product from Example 22, 0.5 g ofn-butylamine and 3 ml of DMPU, under argon, is stirred at roomtemperature for 2 h.

The excess n-butylamine was removed in vacuo and the solids filtered.The filtrate is diluted with a small amount of methanol and the solutionadded dropwise to a mixture of 10 ml of 2-propanol and 120 ml of diethylether. The solution is treated dropwise with 1.0 M hydrogen chloride -diethyl ether solution to afford a yellow solid. The resulting solid iscollected and dried in vacuo to afford 0.175 g of product:

MS (FAB)=m/z 576 (M+H)

Substantially following the method described in detail herein above inExample 57, the compounds of the invention listed below in Examples58-66 are prepared.

EXAMPLE 58[4S-(4α,12aα)]-8-Chloro-4-(dimethylamino)-1,4,4a,5,-5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[(propylamino)acetyl]amino]-2-naphthacenecarboxamidedihydrochloride EXAMPLE 59[4S-(4α,12aα)]-8-Chloro-4-(dimethylamino)-1,4,4a,5,-5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[(pentylamino)acetyl]amino]-2-naphthacenecarboxamidedihydrochloride EXAMPLE 60[4S-(4α,12aα)]-8-Chloro-4-(dimethylamino)-1,4,4a,5,-5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[(methylamino)acetyl]amino]-2-naphthacenecarboxamideand dihydrochloride EXAMPLE 61[4S-(4α,12aα)]-8-Chloro-9-[[(cyclopropylmethylamino)-acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,-12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidedihydrochloride EXAMPLE 62[7S-(7α,10aα)]-N-[9-(Aminocarbonyl)-3-chloro-7-dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-1-pyrrolidineacetamidedihydrochloride EXAMPLE 63[7S-(7α,10aα)]-N-[9-(Aminocarbonyl)-3-chloro-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl-]-1-piperidineacetamidedihydrochloride EXAMPLE 647S-(7α,10aα)]-N-[9-(Aminocarbonyl)-3-chloro-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-5-azabicyclo2.1.1]hexane-5-acetamidedihydrochloride EXAMPLE 65[4S-(4α,12aα)]-8-Chloro-9-[[(cyclobutylamino)acetyl]-amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamidedihydrochloride EXAMPLE 66[7S-(7α,10aα)]-N-[9-(Aminocarbonyl)-3-chloro-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-α-ethyl-1H-imidazole-1-acetamide dihydrochloride

Substantially following the method, described in detail herein above inExample 36, the compounds of the invention listed in Examples 67-68 areprepared from[4S-(4α,12aα)]-9-[(bromopropionyl)amino]-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacene-carboxamide.

EXAMPLE 67[4S-(4α,12aα)]-8-Chloro-9-[[2-(diethylamino)-1-oxo-propyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,-12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 68[7S-(7α,10aα)]-1-[2-[[9-(Aminocarbonyl)-3-chloro-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-napthacenyl]-amino]-1-methyl-2-oxoethyl]prolinemethyl ester EXAMPLE 69[7S-(7α,10aα)]-N-[9-(Aminocarbonyl)-3-chloro-7-dimethylamino-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a-11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-α-(4-hydroxyphenyl)-6-methyl-2,6-diazabicyclo-[2.1.1.]heptane-2-acetamide

The title compound is prepared by the procedure of Example 36 using[4S-(4α,12aα)]-9-[[(4-Hydroxyphenyl)-α-bromoacetyl]amino]-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,-12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideand 6-methyl-2,6-diazabicyclo[2.1.1]heptane.

EXAMPLE 70[4S-(4α,12aα)]-8-Chloro-4-(dimethylamino)-9-[[(dimethylamino)(2-fluorophenyl)acetyl]amino]-1,4,4a,5,-5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide

The title compound is prepared by the procedure of Example 36 using[4S-(4α,12aα)]-9-[[(2-fluorophenyl)-α-bromoacetyl]amino]-8-chloro-4-(dimethylamino)1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideand dimethylamine.

EXAMPLE 71[4S-(4α,12aα)]-8-Chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-9-[[1-(4-methoxy-1-piperazinyl)-4-pentenoyl]amino]-1,11-dioxo-2-naphthacenecarboxamide

The title compound is prepared by the procedure of Example 36 using[4S-(4α,12aα)]-9-[(2-bromo-4-pentenoyl)amino]-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahyroxy-1,11-dioxo-2-naphthacenecarboxamideand 4-methoxypiperazine.

EXAMPLE 72[4S-(4α,12aα)]-8-Chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1-11-dioxo-9-[[1-oxo-4-phenyl-2-[(phenylmethoxy)-amino]butyl]amino]-2-naphthacenecarboxamide

The title compound is prepared by the procedure of Example 36 using[4S-(4α,12aα)]-9-[(α-bromophenylbutyrl)amino]-8-chloro-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideand benzyloxyamine.

EXAMPLE 73[7S-(7α,10aα)]-N-[9-(Aminocarbonyl)-3-chloro-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,8,10a,11-tetrahydroxy-10,12-dioxo-2-naphthacenyl]-α-4-pyridyl-5-azabicyclo[2.1.1]hexan-5-acetamide

The title compound is prepared by the procedure of Example 36 using[4S-(4α,12aα)]-9-[[(4-pyridyl)-α-bromoacetyl]amino]-8-chloro-4-(dimethyl-amino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideand 5-azabicyclo[2.1.1]hexane.

Substantially following the method, described in detail herein above inExample 36, the compounds of the invention listed in Examples 74-75 areprepared from[4S-(4α,12α)]-9-[(bromoacetyl)amino]-4-(dimethylamino)-8-fluoro-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.

EXAMPLE 74[4S-(4α,12aα)]-4-(Dimethylamino)-9-[[(dimethylamino)acetyl]amino]-8-fluoro-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamideEXAMPLE 75[4S-(4α,12aα)]-4-(Dimethylamino)-8-fluoro-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-9-[[(propylamino)acetyl]amino]-2-napthacenecarboxamideEXAMPLE 76[4S-(4α,12aα)]-4-(Dimethylamino)-9-[[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-8-[[(trifluoromethyl)sulfonyl]oxy]-2-naphthacenecarboxamide

The title compound is prepared by the procedure of Example 36 using[4S-(4α,12aα)]-9-[(bromoacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-8-[[(trifluoromethyl)sulfonyl]oxy]-2-naphthacenecarboxamideand dimethylamine.

    ______________________________________                                        MASS SPECTRAL DATA                                                            Example #     MS(FAB):m/z                                                     ______________________________________                                        59            592 (M + H)                                                     60            535 (M + H)                                                     61            575 (M + H)                                                     63            589 (M + H)                                                     ______________________________________                                    

We claim:
 1. A method for the prevention, treatment or control ofbacterial infections in a warm-blooded animal "in need of suchprophylaxis, treatment or control" which comprises administering to saidanimal a pharmacologically effective amount of a compound of theformula: ##STR27## wherein: X is halogen or trifluoromethanesulfonyloxy,the halogen is selected from bromine, chlorine, fluorine and iodine;R isselected from hydrogen; halogen selected from bromine, chlorine,fluorine and iodine; or R=--NR¹ R² and R¹ is selected from hydrogen,methyl, ethyl, n-propyl, 1-methylethyl, n-butyl or 1-methylpropyl and R²is selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl,1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl with the provisothat when R¹ =hydrogen, R² =methyl, ethyl, n-propyl, 1-methylethyl,n-butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl; and whenR¹ =methyl or ethyl, R² =methyl, ethyl, n-propyl, 1-methylethyl,n-butyl, 1-methylpropyl or 2-methylpropyl; and when R¹ =n-propyl, R²=n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl; andwhen R¹ =1-methylethyl, R² =n-butyl, 1-methylpropyl or 2-methylpropyl;and when R¹ =n-butyl, R² =n-butyl, 1-methylpropyl or 2-methylpropyl; andwhen R¹ =1-methylpropyl, R² =2-methylpropyl; R³ is selected fromhydrogen; straight or branched (C₁ -C₈)alkyl group selected from methyl,ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl andoctyl; α-mercapto(C₁ -C₄)alkyl group selected from mercaptomethyl,α-mercaptoethyl, α-mercapto-1-methylethyl, α-mercaptopropyl andα-mercaptobutyl; α-hydroxy-(C₁ -C₄)alkyl group selected fromhydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl, α-hydroxypropyland α-hydroxybutyl; carboxyl (C₁ -C₈)alkyl group; (C₆ -C₁₀)aryl groupselected from phenyl, α-naphthyl and β-naphthyl; substituted(C₆-C₁₀)aryl group with substitution selected from hydroxy, halogen, (C₁-C₄)alkoxy, trihalo(C₁ -C₃)alkyl, nitro, amino, cyano, (C₁-C₄)-alkoxycarbonyl, (C₁ -C₃)alkylamino and carboxy; (C₇ -C₉)aralkylgroup selected from benzyl, 1-phenylethyl, 2-phenylethyl andphenylpropyl; substituted (C₇ -C₉)aralkyl group with substitutionselected from halo, (C₁ -C₄)alkyl, nitro, hydroxy, amino, mono- ordi-substituted (C₁ -C₄) alkylamino, (C₁ -C₄)alkoxy, (C₁ -C.sub.4)alkylsulfonyl, cyano and carboxy; R⁴ is selected from hydrogen and (C₁-C₆)alkyl selected from methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl and hexyl; when R³ does not equal R⁴ thestereochemistry of the carbon bearing the W substituent may be eitherthe racemate (DL) or the individual enantiomers (n or D); W is selectedfrom amino; hydroxylamino; (C₁ -C₁₂) straight or branched alkylmonosubstituted amino group with substitution selected from methyl,ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl,1,1-dimethylethyl, n-pentyl, 2-methylbutyl, 1,1-dimethylpropyl,2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3-methylpentyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 1-methyl-1-ethylpropyl, heptyl, octyl, nonyl, decyl,undecyl and dodecyl and the diastereomers and enantiomers of saidbranched alkyl monosubstituted amino group; (C₃ -C₈)cycloalkylmono-substituted amino group with substitution selected fromcyclopropyl, trans-1,2-dimethylcyclopropyl, cic-1,2-dimethylcyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,bicyclo[2.2.1]hept-2-yl, and bicyclo[2.2.2]oct-2-yl and thediastereomers and enantiomers of said (C₃ -C₈)cycloalkyl monosubstitutedamino; [(C₄ -C₁₀)]cycloalkyl]alkyl monosubstituted amino group withsubstitution selected from (cyclopropyl)methyl, (cyclopropyl)ethyl,(cyclobutyl)methyl, (trans-2-methylcyclopropyl)methyl, and(cis-2-methyl-cyclobutyl)methyl; (C₃ -C₁₀)alkenyl monosubstituted aminogroup with substitution selected from allyl, 3-butenyl, 2-butenyl (cisor trans), 2-pentenyl, 4-octenyl, 2,3-dimethyl-2-butenyl,3-methyl-2-butenyl, 2-cyclopentenyl and 2-cyclohexenyl; (C₆ -C₁₀)arylmonosubstituted amino group with substitution selected from phenyl andnaphthyl; (C₇ -C₁₀)aralkylamino group selected from benzylamino,2-phenylethylamino, 1-phenylethylamino, 2-(naphthyl)methylamino,1-(naphthyl)methylamino and phenylpropylamino; substituted (C.sub. 6-C₁₀)aryl monosubstituted amino group with substitution for the (C₆-C₁₀)aryl group selected from (C₁ -C₅)acyl, (C₁ -C₅) acylamino, (C₁-C₄)alkyl, mono or disubstituted (C₁ -C₈)alkylamino, (C₁ -C₄) alkoxy,(C₁ -C₄)alkoxycarbonyl, (C₁ -C₄)alkylsulfonyl, amino, carboxy, cyano,halogen, hydroxy, nitro and trihalo(C₁ -C₃)alkyl; straight or branchedsymmetrical disubstituted (C₂ -C₁₄) alkylamino group with substitutionselected from dimethyl, diethyl, diisopropyl, di-n-propyl, dibutyl anddiisobutyl; symmetrical disubstituted (C₃ -C₁₄)cycloalkylamino groupwith substitution selected from dicyclopropyl, dicyclobutyl,dicyclopentyl, dicylohexyl and dicycloheptyl; straight or branchedunsymmetrical disubstituted (C₃ -C₁₄)alkylamino group wherein the totalnumber of carbons in the substitution is not more than 14; unsymmetricaldisubstituted (C₄ -C₁₄)cycloalkylamino group wherein the total number ofcarbons in the substitution is not more than 14; (C₂ -C₈)azacyclo- alkyland substituted (C₂ -C₈)azacycloalkyl group selected from aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, 4-methylpiperidinyl,2-methylpyrrolidinyl, cis-3,4-dimethylpyrrolidinyl,trans-3,4-dimethylpyrrolidinyl, 2-azabicyclo[2.1.1]-hex-2-yl,5-azabicyclo[2.1.1]hex-5-yl, 2-azabicyclo[2.2.1]hept-2-yl,7-azabicyclo[2.2.1]hept-7-yl, 2-azabicyclo[2.2.2]oct-2-yl and thediastereomers and enantiomers of said (C₂ -C₈)azacycloalkyl andsubstituted (C₂ -C₈)azacycloalkyl group; 1-azaoxacycloalkyl selectedfrom morpholinyl and 1-aza-5-oxocycloheptane; substituted1-azaoxacycloalkyl group selected from 2-(C₁ -C₃)alkylmorpholinyl, 3-(C₁-C₃)alkylisoxazolidinyl, tetrahydrooxazinyl and 3,4-dihydrooxazinyl;[1,n]-diazacycloalkyl and substituted [1,n]-diazacycloalkyl groupselected from piperazinyl, 2-(C₁ -C₃)alkylpiperazinyl, 4-(C₁-C₃)alkylpiperazinyl, 2,4-dimethylpiperazinyl, 4-(C₁ -C₄)alkoxypiperazinyl, 4-(C₆ -C₁₀)aryloxypiperazinyl, 4-hydroxypiperazinyl,2,5-diazabicyclo[ 2.2.1]hept-2-yl, 2,5-diaza-5-methylbicyclo-[2.2.1]hept-2-yl,2,3-diaza-3-methylbicyclo[2.2.2]oct-2-yl,2,5-diaza-5,7-dimethylbicyclo[2.2.2]oct-2-yl and the diastereomers orenantiomers of said [1,n]-diazacycloalkyl and substituted[1,n]-diazacycloalkyl group; 1-azathiacycloalkyl and substituted1-azathiacycloalkyl group selected from thiomorpholinyl, 2-(C₁-C₃)-alkylthiomorpholinyl and 3-(C₃ -C₆)cycloalkylthiomorpholinyl;N-azolyl and substituted N-azolyl group selected from 1-imidazolyl,2-(C₁ -C₃)alkyl-1-imidazolyl, 3-(C₁ -C₃)alkyl-1-imidazolyl, 1-pyrazolyl,2-(C₁ -C₃) alkyl-1-pyrrolyl, 3-(C₁ -C₃)alkyl-1-pyrazolyl, indolyl,1-(1,2,3-triazolyl), 4-(C₁ -C₃)alkyl-1-(1,2,3-triazolyl), 5-(C₁-C₃)alkyl-1-(1,2,3-triazolyl), 4-(1,2,4-triazolyl), 1-tetrazolyl,2-tetrazolyl and benzimidazolyl; (heterocycle)amino group selected from2- or 3-furanylamino, 2- or 3-thienylamino, 2-, 3- or 4-pyridylamino, 2-or 5-pyridazinylamino, 2-pyrazinylamino, 2-(imidazolyl)amino,(benzimidazolyl)amino, and (benzothiazolyl)amino and substituted(heterocycle)amino group as defined above with substitution selectedfrom straight or branched (C₁ -C₆)alkyl; (heterocycle) methylamino groupselected from 2- or 3-furylmethylamino, 2- or 3-thienylmethylamino, 2-,3- or 4-pyridylmethylamino, 2- or 5-pyridazinylmethylamino,2-pyrazinylmethylamino, 2-(imidazolyl) methylamino,(benzimidazolyl)methylamino, and (benzothiazolyl) methylamino andsubstituted (heterocycle)-methylamino as defined above with substitutionselected from straight or branched (C₁ -C₆)alkyl; carboxy (C₂ -C₄)alkylamino group selected from aminoacetic acid, α-aminopropionic acid,β-aminopropionic acid, α-butyric acid, and β-aminobutyric acid and theenantiomers of said carboxy-(C₂ -C₄) alkylamino group; (C₁-C₄)alkoxycarbonylamino group selected from methoxycarbonylamino,ethoxycarbonylamino, allyloxycarbonylamino, propoxycarbonylamino,isoproproxycarbonylamino, 1,1-dimethylethoxycarbonylamino,n-butoxycarbonylamino, and 2-methylpropoxycarbonylamino; (C₁-C₄)alkoxyamino group selected from methoxyamino, ethoxyamino,n-propoxyamino, 1-methylethoxyamino, n -butoxyamino,2-methylpropoxyamino, and 1,1-dimethylethoxyamino; (C₃ -C₈)cycloalkoxyamino group selected from cyclopropoxyamino,trans-1,2-dimethylcyclopropoxyamino, cis-1,2-dimethyl cyclopropoxyamino,cyclobutoxyamino, cyclopentoxyamino, cyclohexoxyamino,cycloheptoxyamino, cyclooctoxyamino, bicyclo[2.2.1]hept-2-yloxyamino,bicyclo-[2.2.2]oct-2-yloxyamino and the diastereomers and enantiomers ofsaid (C₃ -C₈)cycloalkoxyamino group; (C₆ -C₁₀) aryloxyamino groupselected from phenoxyamino, 1-naphthyloxyamino and 2-naphthyloxyamino;(C₇ -C₁₁) arylalkoxyamino group selected from benzyloxyamino,2-phenylethoxyamino, 1-phenylethoxyamino, 2-(naphthyl) methoxyamino,1-(naphthyl) methoxyamino and phenylpropoxyamino; R⁵ is selected fromhydrogen; straight or branched (C₁ -C₃)alkyl group selected from methyl,ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)aryl group selected fromphenyl, α-naphthyl or β-naphthyl; (C₇ -C₉ ) aralkyl group selected frombenzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocyclegroup selected from a five membered aromatic or saturated ring with oneN, O, S or Se heteroatom optionally having a benzo or pyrido ring fusedthereto selected from pyrrolyl, N-methylindolyl, indolyl,2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,furanyl, benzofuranyl, tetrahydrothienyl, thienyl benzothienyl orselenazolyl, or a five membered aromatic ring with two N, O, S or Seheteroatoms optionally having a benzo or pyrido ring fused theretoselected from imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl,benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl,3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a fivemembered saturated ring with one or two N, O, S or Se heteroatoms and anadjacent appended O heteroatom selected from γ-butyrolactam,γ-butyrolactone, imidazolidinone or N-aminoimidazolidinone, or a sixmembered aromatic ring with one to three N heteroatoms selected frompyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsymtriazinyl,pyrimidinyl or (C₁ -C₃) alkylthio-pyridazinyl, or a six memberedsaturated ring with one or two N, O, S or Se heteroatoms and an adjacentappended O heteroatom selected from 2,3-dioxo-1-dioxo1-piperazinyl,4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3,-dioxo-1-piperazinyl,4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl,2-dioxothiomorpholinyl; or --(CH₂)_(n) COOR⁷ where n=0-4 and R⁷ isselected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; or (C₆ -C₁₀)arylgroup selected from phenyl, α-naphthyl, or β-naphthyl; R⁶ is selectedfrom hydrogen; straight or branched (C₁ -C₃)alkyl group selected frommethyl, ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)aryl group selectedfrom phenyl, α-naphthyl or β-naphthyl; (C₇ -C₉)aralkyl group selectedfrom benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocyclegroup selected from a five membered aromatic or saturated ring with oneN, O, S or Se heteroatom optionally having a benzo or pyrido ring fusedthereto selected from pyrrolyl, N-methylindolyl, indolyl,2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl orselenazolyl, or a five membered aromatic ring with two N, O, S or Seheteroatoms optionally having a benzo or pyrido ring fused theretoselected from imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl,benzoxazolyl, indazolyl, thiazolyl, benzothiazoly,3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a fivemembered saturated ring with one or two N, O, S or Se heteroatoms and anadjacent appended O heteroatom selected from γ-butyrolactam,γ-butyrolactone, imidazolidinone or N-aminoimidazolidinone, or a sixmembered aromatic ring with one to three N heteroatoms selected frompyridyl, pyridazinyl, pyrazinyl, symtriazinyl, unsymtriazinyl,pyrimidinyl or (C₁ -C₃)alkylthiopyridazinyl, or a six membered saturatedring with one or two N, O, S or Se heteroatoms and an adjacent appendedO heteroatom such as 2,3-dioxo-1-piperazinyl,4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl,4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl,2-dioxothiomorpholinyl; or --(CH₂)_(n) COOR⁷ where n=0-4 and R⁷ isselected from hydrogen; straight or branched (C₁ -C₃)alkyl selected frommethyl, ethyl, n-propyl or 1-methylethyl; or (C₆ -C₁₀)aryl selected fromphenyl, α-naphthyl or β-naphthyl; with the proviso that R⁵ and R⁶ cannotboth be hydrogen; or R⁵ and R⁶ taken together are --(CH₂)₂ B(CH₂)₂ --,wherein B is selected from (CH₂)_(m) and m=0-1 --NH, --N(C₁ -C₃)alkyl,straight or branched, --N(C₁ -C₄)alkoxy, oxygen, sulfur or substitutedcongeners selected from (L or D) proline, ethyl(L or D)prolinate,morpholine, pyrrolidine or piperidine; and the pharmacologicallyacceptable organic and inorganic salts or metal complexes.
 2. A methodfor the prevention, treatment or control of bacterial infections in awarm-blooded animal "in need of such prophylaxis, treatment or control"caused by bacteria having the TetM or TetK resistant determinant whichcomprises administering to said animal a pharmacologically evvectiveamount of a compound of the formula: ##STR28## wherein: X is halogen ortrifluoromethanesulfonyloxy, the halogen is selected from bromine,chlorine, fluorine and iodine;R is selected from hydrogen; halogenselected from bromine, chlorine, fluorine and iodine; or R=--NR¹ R² andR¹ is selected from hydrogen, methyl, ethyl, n-propyl, 1-methylethyl,n-butyl or 1-methylpropyl and R² is selected from methyl, ethyl,n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl or1,1-dimethylethyl with the proviso that when R¹ =hydrogen, R² =methyl,ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropylor 1,1-dimethylethyl; and when R¹ =methyl or ethyl, R² =methyl, ethyl,n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl or 2-methylpropyl; andwhen R¹ =n-propyl, R² =n-propyl, 1-methylethyl, n-butyl, 1-methylpropylor 2-methylpropyl; and when R¹ =1-methylethyl, R² =n-butyl,1-methylpropyl or 2-methylpropyl; and when R¹ =n-butyl, R² =n-butyl,1-methylpropyl or 2-methylpropyl; and when R¹ =1-methylpropyl, R²=2-methylpropyl; R³ is selected from hydrogen; straight or branched (C₁-C₈)alkyl group selected from methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl, hexyl, heptyl and octyl; α-mercapto(C₁ -C₄)alkyl groupselected from mercaptomethyl, α-mercaptoethyl, α-mercapto-1-methylethyl,α-mercaptopropyl and α-mercaptobutyl; α-hydroxy-(C₁ -C₄)alkyl groupselected from hydroxymethyl, α-hydroxyethyl, α-hydroxy-1-methylethyl,α-hydroxypropyl and α-hydroxybutyl; carboxyl (C₁ -C₈)alkyl group; (C₆-C₁₀)aryl group selected from phenyl, α-naphthyl and β-naphthyl;substituted(C₆ -C₁₀)aryl group with substitution selected from hydroxy,halogen, (C₁ -C₄)alkoxy, trihalo(C₁ -C₃)alkyl, nitro, amino, cyano, (C₁-C₄)alkoxycarbonyl, (C₁ -C₃)alkylamino and carboxy; (C₇ -C₉)aralkylgroup selected from benzyl, 1-phenylethyl, 2-phenylethyl andphenylpropyl; substituted (C₇ -C₉)aralkyl group with substitutionselected from halo, (C₁ C₄)alkyl, nitro, hydroxy, amino, mono- ordi-substituted (C₁ -C₄) alkylamino, (C₁ -C₄)alkoxy, (C₁-C₄)alkylsulfonyl, cyano and carboxy; R⁴ is selected from hydrogen and(C₁ -C₆)alkyl selected from methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl and hexyl; when R³ does not equal R⁴ thestereochemistry of the carbon bearing the W substituent may be eitherthe racemate (DL) or the individual enantiomers (L or D); W is selectedfrom amino; hydroxylamino; (C₁ -C₁₂) straight or branched alkylmonosubstituted amino group with substitution selected from methyl,ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl,1,1-dimethylethyl, n-pentyl, 2-methylbutyl, 1,1-dimethylpropyl,2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, 1-methylpentyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3-methylpentyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 1-methyl-1-ethylpropyl, heptyl, octyl, nonyl, decyl,undecyl and dodecyl and the diastereomers and enantiomers of saidbranched alkyl monosubstituted amino group; (C₃ --C₈)cycloalkylmono-substituted amino group with substitution selected fromcyclopropyl, trans-1,2-dimethylcyclopropyl, cic-1,2-dimethylcyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,bicyclo[2.2.1]hept-2-yl, and bicyclo[2.2.2]oct-2-yl and thediastereomers and enantiomers of said (C₃ -C₈)cycloalkyl monosubstitutedamino; [(C₄ -C₁₀)]cycloalkyl]alkyl monosubstituted amino group withsubstitution selected from (cyclopropyl)methyl, (cyclopropyl)ethyl,(cyclobutyl)methyl, (trans-2-methylcyclopropyl)methyl, and(cis-2-methyl-cyclobutyl)methyl; (C₃ -C₁₀)alkenyl monosubstituted aminogroup with substitution selected from allyl, 3-butenyl, 2-butenyl (cisor trans), 2-pentenyl, 4-octenyl, 2,3-dimethyl-2-butenyl,3-methyl-2-butenyl, 2-cyclopentenyl and 2-cyclohexenyl; (C₆ -C₁₀)arylmonosubstituted amino group with substitution selected from phenyl andnaphthyl; (C₇ -C₁₀)aralkylamino group selected from benzylamino,2-phenylethylamino, 1-phenylethylamino, 2-(naphthyl)methylamino,1-(naphthyl)methylamino and phenylpropylamino; substituted (C₆ -C₁₀)arylmonosubstitutedamino group with substitution for the (C₆ -C₁₀) arylgroup selected from (C₁ -C₅) acyl, (C₁ -C₅) acylamino, (C₁ -C₄) alkyl,mono or disubstituted (C₁ -C₈) alkylamino, (C₁ -C₄) alkoxy, (C₁ -C₄ )alkoxycarbonyl, (C₁ -C₄ ) alkylsulfonyl, amino, carboxy, cyano, halogen,hydroxy, nitro and trihalo(C₁ -C₃)alkyl; straight or branchedsymmetrical disubstituted (C₂ -C₁₄) alkylamino group with substitutionselected from dimethyl, diethyl, diisopropyl, di-n-propyl, dibutyl anddiisobutyl; symmetrical disubstituted (C₃ -C₁₄)cycloalkylamino groupwith substitution selected from dicyclopropyl, dicyclobutyl,dicyclopentyl, dicylohexyl and dicycloheptyl; straight or branchedunsymmetrical disubstituted (C₃ -C₁₄)alkylamino group wherein the totalnumber of carbons in the substitution is not more than 14; unsymmetricaldisubstituted (C₄ -C₁₄)cycloalkylamino group wherein the total number ofcarbons in the substitution is not more than 14; (C₂ -C₈)azacyclo- alkyland substituted (C₂ -C₈)azacycloalkyl group selected from aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, 4-methylpiperidinyl,2-methylpyrrolidinyl, cis-3,4-dimethylpyrrolidinyl,trans-3,4-dimethylpyrrolidinyl, 2-azabicyclo[2.1.1]-hex-2-yl,5-azabicyclo[2.1.1]hex-5-yl, 2-azabicyclo[2.2.1]hept-2-yl,7-azabicyclo[2.2.1]hept-7-yl, 2-azabicyclo[2.2.2]oct-2-yl and thediastereomers and enantiomers of said (C₂ -C₈)azacycloalkyl andsubstituted (C₂ -C₈)azacycloalkyl group; 1-azaoxacycloalkyl selectedfrom morpholinyl and 1-aza-5-oxocycloheptane; substituted1-azaoxacycloalkyl group selected from 2-(C₁ -C₃)alkylmorpholinyl, 3-(C₁-C₃)alkylisoxazolidinyl, tetrahydrooxazinyl and 3,4-dihydrooxazinyl;[1,n]-diazacycloalkyl and substituted [1,n]-diazacycloalkyl groupselected from piperazinyl, 2-(C₁ -C₃)alkylpiperazinyl, 4-(C₁ -C₃ )alkylpiperazinyl, 2,4-dimethylpiperazinyl, 4-(C₁ -C₄) alkoxypiperazinyl,4-(C₆ -C₁₀)aryloxypiperazinyl, 4-hydroxypiperazinyl,2,5-diazabicyclo[2.2.1]hept-2-yl, 2,5-diaza-5-methylbicyclo-[2.2.1]hept-2-yl,2,3-diaza-3-methylbicyclo[2.2.2]oct-2-yl,2,5-diaza-5,7-dimethylbicyclo[2.2.2]oct-2-yl and the diastereomers orenantiomers of said [1,n]-diazacycloalkyl and substituted[1,n]-diazacycloalkyl group; 1-azathiacycloalkyl and substituted1-azathiacycloalkyl group selected from thiomorpholinyl, 2-(C₁-C₃)-alkylthiomorpholinyl and 3-(C₃ -C₆)cycloalkylthiomorpholinyl;N-azolyl and substituted N-azolyl group selected from 1-imidazolyl,2-(C₁ -C₃)alkyl-1-imidazolyl, 3-(C₁ -C₃)alkyl-1-imidazolyl, 1-pyrazolyl,2-(C₁ -C₃) alkyl-1-pyrrolyl, 3-(C₁ -C₃)alkyl-1-pyrazolyl, indolyl,1-(1,2,3-triazolyl), 4-(C₁ -C₃)alkyl-1-(1,2,3-triazolyl), 5-(C₁-C₃)alkyl-1-(1,2,3-triazolyl), 4-(1,2,4-triazolyl), 1-tetrazolyl,2-tetrazolyl and benzimidazolyl; (heterocycle)amino group selected from2- or 3-furanylamino, 2- or 3-thienylamino, 2-, 3- or 4-pyridylamino, 2-or 5-pyridazinylamino, 2-pyrazinylamino, 2-(imidazolyl)amino,(benzimidazolyl)amino, and (benzothiazolyl)amino and substituted(heterocycle) amino group as defined above with substitution selectedfrom straight or branched (C₁ -C₆)alkyl; (heterocycle) methylamino groupselected from 2- or 3-furylmethylamino, 2- or 3-thienylmethylamino, 2-,3- or 4-pyridylmethylamino, 2- or 5-pyridazinylmethylamino,2-pyrazinylmethylamino, 2-(imidazolyl) methylamino,(benzimidazolyl)methylamino, and (benzothiazolyl) methylamino andsubstituted (heterocycle)-methylamino as defined above with substitutionselected from straight or branched (C₁ -C₆)alkyl; carboxy(C₂-C₄)alkylamino group selected from aminoacetic acid, α-aminopropionicacid, β-aminopropionic acid, α-butyric acid, and β-aminobutyric acid andthe enantiomers of said carboxy-(C₂ -C₄) alkylamino group; (C₁-C₄)alkoxycarbonylamino group selected from methoxycarbonylamino,ethoxycarbonylamino, allyloxycarbonylamino, propoxycarbonylamino,isoproproxycarbonylamino, 1,1-dimethylethoxycarbonylamino,n-butoxycarbonylamino, and 2-methylpropoxycarbonylamino; (C₁-C₄)alkoxyamino group selected from methoxyamino, ethoxyamino,n-propoxyamino, 1-methylethoxyamino, n-butoxyamino,2-methylpropoxyamino, and 1,1-dimethylethoxyamino; (C₃-C₈)cycloalkoxyamino group selected from cyclopropoxyamino,trans-1,2-dimethylcyclopropoxyamino,cis-1,2-dimethylcyclopropoxyamino,cyclobutoxyamino, cyclopentoxyamino, cyclohexoxyamino,cycloheptoxyamino, cyclocctoxyamino, bicyclo[2.2.1]hept-2-yloxyamino,bicyclo-[2.2.2]oct-2-yloxyamino and the diastereomers and enantiomers ofsaid (C₃ -C₈)cycloalkoxyamino group; (C₆ -C₁₀) aryloxyamino groupselected from phenoxyamino, 1-naphthyloxyamino and 2-naphthyloxyamino;(C₇ - C₁₁)arylalkoxyamino group selected from benzyloxyamino,2-phenylethoxyamino, 1-phenylethoxyamino, 2-(naphthyl) methoxyamino,1-(naphthyl)methoxyamino and phenylpropoxyamino; R⁵ is selected fromhydrogen; straight or branched (C₁ -C₃)alkyl group selected from methyl,ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)aryl group selected fromphenyl, α-naphthyl or β-naphthyl; (C₇ -C₉)aralkyl group selected frombenzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocyclegroup selected from a five membered aromatic or saturated ring with oneN, O, S or Se heteroatom optionally having a benzo or pyrido ring fusedthereto selected from pyrrolyl, N-methylindolyl, indolyl,2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,furanyl, benzofuranyl, tetrahydrothienyl, thienyl benzothienyl orselenazolyl, or a five membered aromatic ring with two N, O, S or Seheteroatoms optionally having a benzo or pyrido ring fused theretoselected from imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl,benzoxazolyl, indazolyl, thiazolyl, benzothiazolyl,3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a fivemembered saturated ring with one or two N, O, S or Se heteroatoms and anadjacent appended O heteroatom selected from γ-butyrolactam,γ-butyrolactone, imidazolidinone or N-aminoimidazolidinone, or a sixmembered aromatic ring with one to three N heteroatoms selected frompyridyl, pyridazinyl, pyrazinyl, sym-triazinyl, unsymtriazinyl,pyrimidinyl or (C₁ -C₃) alkylthio-pyridazinyl, or a six memberedsaturated ring with one or two N, O, S or Se heteroatoms and an adjacentappended O heteroatom selected from 2,3-dioxo-1-piperazinyl,4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl,4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl,2-dioxothiomorpholinyl; or --(CH₂)_(n) COOR⁷ where n=0-4 and R⁷ isselected from hydrogen; straight or branched (C₁ -C₃)alkyl groupselected from methyl, ethyl, n-propyl or 1-methylethyl; or (C₆ -C₁₀)arylgroup selected from phenyl, α-naphthyl, or β-naphthyl; R⁶ is selectedfrom hydrogen; straight or branched (C₁ -C₃)alkyl group selected frommethyl, ethyl, n-propyl or 1-methylethyl; (C₆ -C₁₀)aryl group selectedfrom phenyl, α-naphthyl or β-naphthyl; (C₇ -C₉)aralkyl group selectedfrom benzyl, 1-phenylethyl, 2-phenylethyl or phenylpropyl; a heterocyclegroup selected from a five membered aromatic or saturated ring with oneN, O, S or Se heteroatom optionally having a benzo or pyrido ring fusedthereto selected from pyrrolyl, N-methylindolyl, indolyl,2-pyrrolidinyl, 3-pyrrolidinyl, 2-pyrrolinyl, tetrahydrofuranyl,furanyl, benzofuranyl, tetrahydrothienyl, thienyl, benzothienyl orselenazolyl, or a five membered aromatic ring with two N, O, S or Seheteroatoms optionally having a benzo or pyrido ring fused theretoselected from imidazolyl, pyrazolyl, benzimidazolyl, oxazolyl,benzoxazolyl, indazolyl, thiazolyl, benzothiazoly,3-alkyl-3H-imidazo[4,5-b]pyridyl or pyridylimidazolyl, or a fivemembered saturated ring with one or two N, O, S or Se heteroatoms and anadjacent appended O heteroatom selected from γ-butyrolactam,γ-butyrolactone, imidazolidinone or N-aminoimidazolidinone, or a sixmembered aromatic ring with one to three N heteroatoms selected frompyridyl, pyridazinyl, pyrazinyl, symtriazinyl, unsymtriazinyl,pyrimidinyl or (C₁ -C₃)alkylthiopyridazinyl, or a six membered saturatedring with one or two N, O, S or Se heteroatoms and an adjacent appendedO heteroatom such as 2,3-dioxo-1-piperazinyl,4-ethyl-2,3-dioxo-1-piperazinyl, 4-methyl-2,3-dioxo-1-piperazinyl,4-cyclopropyl-2-dioxo-1-piperazinyl, 2-dioxomorpholinyl,2-dioxothiomorpholinyl; or --(CH₂)_(n) COOR⁷ where n=0-4 and R⁷ isselected from hydrogen; straight or branched (C₁ -C₃)alkyl selected frommethyl, ethyl, n-propyl or 1-methylethyl; or (C₆ -C₁₀)aryl selected fromphenyl, α-naphthyl or β-naphthyl; with the proviso that R⁵ and R⁶ cannotboth be hydrogen; or R⁵ and R⁶ taken together are --(CH₂)₂ B(CH₂)₂ --,wherein B is selected from (CH₂)_(m) and m=0-1, --NH, --N (C₁ -C₃)alkyl,straight or branched, --N(C₁ -C₄)alkoxy, oxygen, sulfur or substitutedcongeners selected from (L or D) proline, ethyl(L or D)prolinate,morpholine, pyrrolidine or piperidine; and the pharmacologicallyacceptable organic and inorganic salts or metal complexes.